Compositions and methods for cystic fibrosis therapy

Abstract

Compositions and methods for therapy of cystic fibrosis and other conditions are provided. The compositions comprise one or more flavones and/or isoflavones capable of stimulating chloride transport in epithelial tissues. Therapeutic methods involve the administration (e.g., orally or via inhalation) of such compositions to a patient afflicted with cystic fibrosis and/or another condition responsive to stimulation of chloride transport.

Description

TECHNICAL FIELD

The present invention relates generally to the treatment of cystic fibrosis. The invention is more particularly related to compositions comprising one or more flavones and/or isoflavones, which may be used to activate chloride transport (ie., absorption and/or secretion) in epithelial tissues of the airways, the intestine, the pancreas and other exocrine glands, and for cystic fibrosis therapy.

BACKGROUND OF THE INVENTION

Cystic fibrosis is a lethal genetic disease afflicting approximately 30,000 individuals in the United States. Approximately 1 in 2500 caucasians is born with the disease, making it the most common lethal, recessively inherited disease in that population.

Cystic fibrosis affects the secretory epithelia of a variety of tissues, altering the transport of water, salt and other solutes into and out of the blood stream. In particular, the ability of epithelial cells in the airways, pancreas and other tissues to transport chloride ions, and accompanying sodium and water, is severely reduced in cystic fibrosis patients, resulting in respiratory, pancreatic and intestinal ailments. The principle clinical manifestation of cystic fibrosis is the resulting respiratory disease, characterized by airway obstruction due to the presence of a thick mucus that is difficult to clear from airway surfaces. This thickened airway liquid contributes to recurrent bacterial infections and progressively imparied respiration, eventually resulting in death.

In cystic fibrosis, defective chloride transport is generally due to a mutation in a chloride channel known as the cystic fibrosis transmembrane conductance regulator (CFTR; see Riordan et al., Science 245:1066-73, 1989). CFTR is a linear chloride channel found in the plasma membrane of certain epithelial cells, where it regulates the flow of chloride ions in response to phosphorylation by a cyclic AMP-dependent kinase. Many mutations of CFTR have been reported, the most common of which is a deletion of phenylalanine at position 508 (.DELTA.F508-CFTR), which is present in approximately 70% of patients with cystic fibrosis. A glycine to aspartate substitution at position 551 (G55 ID-CFTR) occurs in approximately 1% of cystic fibrosis patients.

Current treatments for cystic fibrosis generally focus on controlling infection through antibiotic therapy and promoting mucus clearance by use of postural drainage and chest percussion. However, even with such treatments, frequent hospitalization is often required as the disease progresses. New therapies designed to increase chloride ion conductance in airway epithelial cells have been proposed, but their long term beneficial effects have not been established and such therapies are not presently available to patients.

Accordingly, improvements are needed in the treatment of cystic fibrosis. The present invention fulfills this need and further provides other related advantages.

SUMMARY OF THE INVENTION

Briefly stated, the present invention provides compositions and methods for the therapy of cystic fibrosis. Within one aspect, the present invention provides methods for enhancing chloride transport in epithelial cells, comprising contacting epithelial cells with a compound selected from the group consisting of flavones and isoflavones, wherein the compound is capable of stimulating chloride transport, and wherein the compound is not genistein. Within certain embodiments, the compound is quercetin, apigenin, kaempferol or biochanin A. For enhancing chloride transport in airway epithelial cells of a mammal, compounds may be administered orally or by inhalation.

Within other aspects, the present invention provides methods for treating cystic fibrosis in a patient, comprising administering a compound selected from the group consisting of flavones and isoflavones, wherein the compound is capable of stimulating chloride transport, and wherein the compound is not genistein. Within certain embodiments, the compound is quercetin, apigenin, kaempferol or biochanin A. Compounds may be administered orally or by inhalation.

Within further related aspects, the present invention provides methods for increasing chloride ion conductance in airway epithelial cells of a patient afflicted with cystic fibrosis, wherein the patient's CFTR protein has a deletion at position 508, the method comprising administering to a mammal one or more compounds selected from the group consisting of flavones and isoflavones, wherein the compound is capable of stimulating chloride secretion.

Within further aspects, pharmaceutical compositions for treatment of cystic fibrosis are provided, comprising one or more flavones or isoflavones capable of stimulating chloride transport in combination with a pharmaceutically acceptable carrier. Within certain embodiments, such compositions may comprise quercetin, apigenin, kaempferol and/or biochanin A in combination with a pharmaceutically acceptable carrier.

These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed herein are hereby incorporated by reference in their entirety as if each was incorporated individually.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a recording of transepithelial short-circuit current (Y axis) as a function of time (X axis), showing the effect of apigenin on the current across a Calu-3 cell monolayer. Measurements were performed in an Ussing chamber, where the basolateral membrane was permeabilized with .alpha.-toxin and a chloride gradient was applied across the apical membrane as a driving force. Tissue was first stimulated with cAMP (100 .mu.M). Apigenin (50 .mu.M) was subsequently added as indicated. The horizontal bar represents 100 seconds, and the vertical bar represents 12 .mu.A/cm.sup.2.

FIG. 2 is a recording showing the effect of quercetin on transepithelial short-circuit current across a Calu-3 cell monolayer in an Ussing chamber, where the basolateral membrane was permeabilized with .alpha.-toxin and a chloride gradient was applied across the apical membrane as a driving force. Tissue was first stimulated with cAMP (100 .mu.M). Quercetin (30 .mu.M) was subsequently added as indicated. Bars are 140 seconds (horizontal) and 12 .mu.A/cm.sup.2 (vertical).

FIG. 3 is a recording illustrating the dose-dependent stimulation of transepithelial chloride secretion by quercetin (in the amounts indicated) across a primary bovine tracheal epithelium. Amiloride (50 .mu.M) was added to block sodium transport as indicated. The CFTR channel blocker diphenylcarboxylate (DPC, 5 mM) was added as shown.

FIG. 4 is a recording showing the effect of biochanin A on transepithelial short-circuit current across a Calu-3 cell monolayer in an Ussing chamber, where the basolateral membrane was permeabilized with .alpha.-toxin and a chloride gradient was applied across the apical membrane as a driving force. The tissue was first stimulated with forskolin (Fsk, 10 .mu.M). Subsequent addition of biochanin A (Bio, 100 and 300 .mu.M) was subsequently added as indicated.

FIG. 5 is a cell-attached single channel patch clamp recording from a 3T3 cell expressing .DELTA.F508-CFTR. The cell was treated with 10 .mu.M forskolin as shown. Genistein (50 .mu.M) and apigenin (50 .mu.M), were added where indicated by boxes. The holding potential was 75 mV, and channel openings were upward.

FIG. 6 is a whole cell patch clamp recording on an airway epithelial cell homozygous for .DELTA.F508-CFTR. Before the measurement, the cell was incubated for 2 days in 5 mM 4-phenylbutyrate. 30 .mu.M quercetin was added where indicated by the box. Further stimulation by forskolin (10 .mu.M) is also shown. The holding potential was -60 mV.

FIG. 7 is a recording illustrating the effect of genistein on G551D-CFTR expressed in a Xenopus oocyte. Current was measured with the two-electrode voltage clamp technique. G551D-CFTR was injected in oocyte. Current was first stimulated with forskolin (10 .mu.M) and isobutylmethylxantine (IBMX; 2 mM). Genistein (50 .mu.M) was added as indicated. The right panel shows current voltage relations recorded after treatment with forskolin and IBMX (F/I) and after treatment with genistein (F/I+Geni). A voltage ramp from -130 mV to +70 mV was applied and current was recorded during the two conditions.

FIG. 8 is a recording illustrating the effect of quercetin on nasal potential difference (PD) measurement in a healthy human volunteer. Amiloride (50 .mu.M) was added to block sodium transport as indicated. Conditions were rendered chloride free (Cl free) and chloride secretion was stimulated with isoproterenol (iso; 5 .mu.M). Quercetin (querc; 10 .mu.M) was added as indicated.

FIG. 9 is a recording illustrating the effect of apigenin and kaempferol on nasal PD in mice. Chloride secretion was stimulated with isoproterenol (iso; 5 .mu.M), and amiloride (50 .mu.M) was added to block sodium transport as indicated. Under chloride-free conditions (Cl free), apigenin (50 .mu.M, left panel) and kaempferol (kaemp, 50 .mu.M, right panel) were added as indicated.

DETAILED DESCRIPTION OF THE INVENTION

As noted above, the present invention is generally directed to compositions and methods for the treatment of diseases characterized by defective chloride transport in epithelial tissues, including cystic fibrosis, and diseases with excessive accumulation of mucus, including cystic fibrosis, chronic bronchitis and asthma. It has been found, within the context of the present invention, that certain flavones and isoflavones are capable of stimulating chloride transport in epithelial tissues (e.g., tissues of the airways, intestine, pancreas and other exocrine glands) in a cyclic-AMP independent manner. Such therapeutic compounds may be administered to patients afflicted with cystic fibrosis as described herein.

The term "flavones", as used herein refers to a compound based on the core structure of flavone: ##STR1##

An "isoflavone" is an isomer of a flavone (i.e., the phenyl moiety at position 2 is moved to position 3), and having the core structure shown below: ##STR2##

Many flavones are naturally-occurring compounds, but synthetic flavones and isoflavones are also encompassed by the present invention. A flavone or isoflavone may be modified to comprise any of a variety of functional groups, such as hydroxyl and/or ether groups. Preferred flavones comprise one or more hydroxyl groups, such as the trihydroxyflavone apigenin, the tetrahydroxyflavone kaempferol and the pentahydroxyflavone quercetin. Preferred isoflavones comprise one or more hydroxyl and/or methoxy groups, such as the methoxy, dihydroxy isoflavone biochanin A.

Flavones and isoflavones for use within the context of the present invention have the ability to stimulate chloride transport in epithelial tissues. Such transport may result in secretion or absorption of chloride ions. The ability to stimulate chloride transport may be assessed using any of a variety of systems. For example, in vitro assays using a mammalian trachea or a cell line, such as the permanent airway cell line Calu-3 (ATCC Accession Number HTB55) may be employed. Alternatively, the ability to stimulate chloride transport may be evaluated within an in vivo assay employing a mammalian nasal epithelium. In general, the ability to stimulate chloride transport may be assessed by evaluating CFTR-mediated currents across a membrane by employing standard Ussing chamber (see Ussing and Zehrahn, Acta. Physiol Scand. 23:110-127, 1951) or nasal potential difference measurements (see Knowles et al., Hum. Gene Therapy 6:445-455, 1995). Within such assays, a flavone or isoflavone that stimulates a statistically significant increase in chloride transport at a concentration of about 1-300 .mu.M is said to stimulate chloride transport.

Within one in vitro assay, the level of chloride transport may be evaluated using mammalian pulmonary cell lines, such as Calu-3 cells, or primary bovine tracheal cultures. In general, such assays employ cell monolayers, which may be prepared by standard cell culture techniques. Within such systems, CFTR-mediated chloride current may be monitored in an Ussing chamber using intact epithelia. Alternatively, chloride transport may be evaluated using epithelial tissue in which the basolateral membrane is permeabilized with Staphylococcus aureus .alpha.-toxin, and in which a chloride gradient is imposed across the apical membrane (see Illek et al., Am. J. Physiol. 270:C265-75, 1996). In either system, chloride transport is evaluated in the presence and absence of a test compound (i.e., a flavone or isoflavone), and those compounds that stimulate chloride transport as described above may be used within the methods provided herein.

Within another in vitro assay for evaluating chloride transport, cells are transfected with a chloride channel gene (e.g., CFTR) having a mutation associated with cystic fibrosis. Any CFTR gene that is altered relative to the normal human sequence provided in SEQ ID NO: 1, such that the encoded protein contains a mutation associated with cystic fibrosis, may be employed within such an assay. The most common disease-causing mutation in cystic fibrosis is a deletion of phenylalanine at position 508 in the CFTR protein (.DELTA.F508-CFTR; SEQ ID NO:4). Accordingly, the use of a CFTR gene encoding .DELTA.F508-CFTR is preferred. However, genes encoding other altered CFTR proteins (e.g., G551D-CFTR; SEQ ID NO:6) may also be used. Cells such as NIH 3T3 fibroblasts may be transfected with an altered CTFR gene, such as .DELTA.F508-CFTR, using well known techniques (see Anderson et al., Science 25:679-682, 1991). The effect of a compound on chloride transport in such cells may be evaluated by monitoring CFTR-mediated currents using the patch clamp method (see Hamill et al., Pflugers Arch. 391:85-100, 1981) with and without compound application.

Within another in vitro assay, a mutant CFTR may be microinjected into cells such as Xenopus oocytes. Chloride conductance mediated by the CFTR mutant in the presence and absence of a test compound may be monitored with the two electrode voltage clamp method (see Miledi et al., Proc. R. Soc. Lond. Biol. 218:481-484, 1983).

Alternatively, such assays may be performed using a mammalian trachea, such as a primary cow tracheal epithelium using the Ussing chamber technique as described above. Such assays are performed in the presence and absence of test compound to identify flavone and isoflavones that stimulate chloride transport.

In vivo, chloride secretion may be assessed using measurements of nasal potential differences in a mammal, such as a human or a mouse. Such measurements may be performed on the inferior surface of the inferior turbinate following treatment of the mucosal surface with a test compound during perfusion with the sodium transport blocker amiloride in chloride-free solution. The nasal potential difference is measured as the electrical potential measured on the nasal mucosa with respect to a skin electrode placed on a slightly scratched skin part (see Alton et al., Eur. Respir. J. 3:922-926, 1990) or with respect to a subcutaneous needle (see Knowles et al., Hum. Gene Therapy 6:445-455, 1995). Nasal potential difference is evaluated in the presence and absence of test compound, and those compounds that results in a statistically significant increase in nasal potential difference stimulate chloride transport.

As noted above, any flavone or isoflavone that stimulates chloride transport within at least one of the above assays may be used for therapy of cystic fibrosis, other diseases characterized by abnormally high mucus accumulation in the airways or intestinal disorders such as constipation. Preferred therapeutic compounds include quercetin (3,3',4',5,7-pentahydroxyflavone), apigenin (4'5,7-trihydroxyflavone), kaempferol (3,4',5,7-tetrahydroxyflavone) and biochanin A (4'-methoxy-5,7-dihydroxyisoflavone), as depicted below: ##STR3##

Other suitable therapeutic compounds may be identified using the representative assays as described herein.

Quercetin, apigenin, kaempferol, biochanin A and other flavones and isoflavones may generally be prepared using well known techniques, such as those described by Shakhova et al., Zh. Obshch. Khim. 32:390, 1962; Farooq et al., Arch. Pharm. 292:792, 1959; and Ichikawa et al., Org. Prep. Prog. Int. 14:183, 1981. Alternatively, such compounds may be commercially available (e.g., from Indofine Chemical Co., Inc., Somerville, N.J. or Sigma-Aldrich, St. Louis, Mo.). Further modifications to such compounds may be made using conventional organic chemistry techniques, which are well known to those of ordinary skill in the art.

For in vivo use, a therapeutic compound as described herein is generally incorporated into a pharmaceutical composition prior to administration. Within such compositions, one or more therapeutic compounds as described herein are present as active ingredient(s) (ie., are present at levels sufficient to provide a statistically significant effect on nasal potential difference, as measured using a representative assay as provided herein). A pharmaceutical composition comprises one or more such compounds in combination with any pharmaceutically acceptable carrier(s) known to those skilled in the art to be suitable for the particular mode of administration. In addition, other pharmaceutically active ingredients (including other therapeutic agents) may, but need not, be present within the composition.

Administration may be achieved by a variety of different routes. One preferred route is oral administration of a composition such as a pill, capsule or suspension. Such compositions may be prepared according to any method known in the art, and may comprise any of a variety of inactive ingredients. Suitable excipients for use within such compositions include inert diluents (which may be solid materials, aqueous solutions and/or oils) such as calcium or sodium carbonate, lactose, calcium or sodium phosphate, water, arachis oil, peanut oil liquid paraffin or olive oil; granulating and disintegrating agents such as maize starch, gelatin or acacia and/or lubricating agents such as magnesium stearate, stearic acid or talc. Other inactive ingredients that may, but need not, be present include one or more suspending agents (e.g., sodium carboxymethylcellulose, methylcellulose, hydroxypropylmethylcellulose, sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia), thickeners (e.g., beeswax, paraffin or cetyl alcohol), dispersing or wetting agents, preservatives (e.g., antioxidants such as ascorbic acid), coloring agents, sweetening agents and/or flavoring agents.

A pharmaceutical composition may be prepared with carriers that protect active ingredients against rapid elimination from the body, such as time release formulations or coatings. Such carriers include controlled release formulations, such as, but not limited to, microencapsulated delivery systems, and biodegradable, biocompatible polymers, such as ethylene vinyl acetate, polyanhydrides, polyglycolic acid, polyorthoesters, polylactic acid and others known to those of ordinary skill in the art.

Particularly preferred are methods in which the therapeutic compound(s) are directly administered as a pressurized aerosol or nebulized formulation to the patient's lungs via inhalation. Such formulations may contain any of a variety of known aerosol propellants useful for endopulmonary and/or intranasal inhalation administration. In addition, water may be present, with or without any of a variety of cosolvents, surfactants, stabilizers (e.g., antioxidants, chelating agents, inert gases and buffers). For compositions to be administered from multiple dose containers, antimicrobial agents are typically added. Such compositions are also generally filtered and sterilized, and may be lyophilized to provide enhanced stability and to improve solubility.

Pharmaceutical compositions are administered in an amount, and with a frequency, that is effective to inhibit or alleviate the symptoms of cystic fibrosis and/or to delay the progression of the disease. The effect of a treatment may be clinically determined by nasal potential difference measurements as described herein. The precise dosage and duration of treatment may be determined empirically using known testing protocols or by testing the compositions in model systems known in the art and extrapolating therefrom. Dosages may also vary with the severity of the disease. A pharmaceutical composition is generally formulated and administered to exert a therapeutically useful effect while minimizing undesirable side effects. In general, an oral dose ranges from about 200 mg to about 1000 mg, which may be administered 1 to 3 times per day. Compositions administered as an aerosol are generally designed to provide a final concentration of about 10 to 50 .mu.M at the airway surface, and may be administered 1 to 3 times per day. It will be apparent that, for any particular subject, specific dosage regimens may be adjusted over time according to the individual need.

As noted above, a pharmaceutical composition may be administered to a mammal to stimulate chloride transport, and to treat cystic fibrosis. Patients that may benefit from administration of a therapeutic compound as described herein are those afflicted with cystic fibrosis. Such patients may be identified based on standard criteria that are well known in the art, including the presence of abnormally high salt concentrations in the sweat test, the presence of high nasal potentials, or the presence of a cystic fibrosis-associated mutation. Activation of chloride transport may also be beneficial in other diseases that show abnormally high mucus accumulation in the airways, such as asthma and chronic bronchitis. Similarly, intestinal constipation may benefit from activation of chloride transport by a flavone or isoflavone as provided herein.

Summary of Sequence Listing

SEQ ID NO:1 is a DNA sequence encoding human CFTR.

SEQ ID NO:2 is an amino acid sequence of human CFTR.

SEQ ID NO:3 is a DNA sequence encoding human CFTR with the .DELTA.F508 mutation.

SEQ ID NO:4 is an amino acid sequence of human CFTR with the .DELTA.F508 mutation.

SEQ ID NO:5 is a DNA sequence encoding human CFTR with the G551D mutation.

SEQ ID NO:6 is an amino acid sequence of human CFTR with the G55ID mutation.

The following Examples are offered by way of illustration and not by way of limitation.

EXAMPLES

Example 1

Stimulation of Chloride Transport by Representative Flavones and Isoflavones in Airway Cells

This Example illustrates the use of the representative compounds apigenin, quercetin and biochanin A to enhance chloride secretion in Calu-3 human pulmonary cultures or in primary bovine tracheal cultures.

A Calu-3 cell monolayer was prepared in an Ussing chamber as described by Illek et al., Am. J. Physiol. 270:C265-275, 1996. The basolateral membrane was permeabilized with .alpha.-toxin and a chloride gradient was applied across the apical membrane as a driving force (see Illek et al, Am. J. Physiol. 2,70:C265-C275, 1996). The tissue was first stimulated with cAMP (100 .mu.M), and then with a representative flavone or isoflavone.

As shown in FIGS. 1 and 2, subsequent addition of apigenin or quercetin further stimulated chloride current. FIG. 1 illustrates the short circuit current across the Calu-3 cell monolayer before and after addition of apigenin (50 .mu.M). FIG. 2 illustrates the effect of quercetin (30 .mu.M) on chloride current across a Calu-3 monolayer. In both cases, the flavone stimulated chloride current beyond the stimulation achieved by cAMP.

FIG. 3 illustrates the results of a related experiment to evaluate the dose-dependent stimulation of transepithelial chloride secretion by quercetin across a primary bovine tracheal epithelium. The epithelial cells were first treated with amiloride (50 .mu.M), and then with quercetin at the indicated concentrations. The dose-response relation yielded a halfinaximal stimulation at 12.5 .mu.M. At high concentrations of quercetin, the current was blocked. Current was fully inhibited by the CFTR channel blocker diphenylcarboxylate (DPC, 5 mM).

To evaluate the effect of biochanin A, a Calu-3 cell monolayer was prepared and permeabilized as described above. The tissue was first stimulated with with forskolin (Fsk, 10 .mu.M). The effect of biochanin A (Bio, 100 and 300 .mu.M) on short-circuit current (I.sub.sc) across the Calu-3 monolayer was evaluated in an Ussing chamber. As shown in FIG. 4, biochanin A further stimulated chloride secretion.

Example 2

Activation of Mutant CFTR by Representative Flavones and Isoflavones

This Example illustrates the use of the representative compounds apigenin, quercetin and genistein to activate .DELTA.F508-CFTR and G551D-CFTR in different cell types.

A cell-attached single channel patch clamp recording was obtained from a 3T3 cell expressing .DELTA.F508-CFTR as described by Hamill et al., Pflugers Arch. 391:85-100, 1981 and Fischer and Machen, J. Gen. Physiol. 104:541-566, 1994. As shown in FIG. 5, stimulation of the cell with 10 .mu.M forskolin did not activate .DELTA.F508-CFTR channel, but addition of genistein (50 .mu.M) or apigenin (50 .mu.M, where indicated by boxes) induced .DELTA.F508-CFTR channel openings, and removal of these compounds inactivated the channels. The holding potential was 75 mV, and channel openings were upward.

FIG. 6 presents a whole cell patch clamp recording on an airway epithelial cell homozygous for .DELTA.F508-CFTR (cell type: JME cell, see Jeffersen et al., Am. J. Physiol. 259:L496-L505, 1990). Before the measurement, the cell was incubated for 2 days in 5 mM 4-phenylbutyrate to enhance .DELTA.F508-CFTR expression in the plasma membrane (Rubenstein & Zeitlin, Ped. Pulm. Suppl. 12:234, 1995). Measurements were performed as described by Fischer et al., J. Physiol. Lond. 489:745-754, 1995. Addition of 30 .mu.M quercetin activated chloride current in the whole cell mode, which was further stimulated by forskolin. The holding potential was -60 mV.

The effect of genistein on chloride current in a Xenopus oocyte expressing G551D-CFTR was measured with the two-electrode voltage clamp technique (see Miledi et al., Proc. R. Soc. Lond Biol. 218:481-484, 1983). G55ID-CFTR (2 ng in 50 nL of water) was injected into the oocyte. Current was first stimulated with forskolin (10 .mu.M) and isobutylmethylxantine (IBMX; 2 mM). Genistein (50 .mu.M) was found to further activate chloride currents. As shown in FIG. 7, genistein increased conductance and shifted reversal potential to the right, which is indicative of a stimulated chloride current.

Example 3

Effect of Representative Flavones on Nasal Potential Difference

This Example illustrates the in vivo use of quercetin, apigenin and kaempferol to activate the nasal potential difference in humans and mice. The effect of quercetin on nasal potential difference (PD) measurement in a healthy human volunteer was measured as described by Knowles et al., Hum. Gene Therapy 6:445-455, 1995. Under conditions where sodium transport was blocked with amiloride (50 .mu.M) and chloride secretion was stimulated under chloride-free conditions with isoproterenol (5 .mu.M), quercetin (10 .mu.M) stimulated nasal PD further (FIG. 8).

The effect of apigenin and kaempferol on nasal PD in mice was evaluated using a method similar to that employed for measurements in humans, except that a plastic tube of approximately 0.1 mm diameter was used as an exploring nasal electrode. The plastic tube was perfused with test solutions at approximately 10 .mu.L/min. After blocking sodium transport with amiloride (50 .mu.M) and during stimulation of chloride secretion with isoproterenol (iso;5 .mu.M) under chloride-free conditions, apigenin (50 .mu.M, left panel) and kaempferol (kaemp, 50 .mu.M, right panel) further stimulated nasal PD.

These results show that the representative flavonoids quercetin, apigenin, kaempferol and biochanin A stimulate chloride transport across epithelial tissues derived from the airways in vitro, and across nasal epithelium in vivo. The results also show that the CFTR mutants .DELTA.F508 and G551D can be activated by the representative compounds genistein and apigenin.

From the foregoing, it will be appreciated that, although specific embodiments of the invention have been described herein for the purpose of illustration, various modifications may be made without deviating from the spirit and scope of the invention.

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#A GAA TGG GAT AGA GAG 312Ser Ala Asp Asn Leu Ser Glu Lys Leu Glu Ar - #g Glu Trp Asp Arg Glu# 60- CTG GCT TCA AAG AAA AAT CCT AAA CTC ATT AA - #T GCC CTT CGG CGA TGT 360Leu Ala Ser Lys Lys Asn Pro Lys Leu Ile As - #n Ala Leu Arg Arg Cys# 75- TTT TTC TGG AGA TTT ATG TTC TAT GGA ATC TT - #T TTA TAT TTA GGG GAA 408Phe Phe Trp Arg Phe Met Phe Tyr Gly Ile Ph - #e Leu Tyr Leu Gly Glu# 90- GTC ACC AAA GCA GTA CAG CCT CTC TTA CTG GG - #A AGA ATC ATA GCT TCC 456Val Thr Lys Ala Val Gln Pro Leu Leu Leu Gl - #y Arg Ile Ile Ala Ser# 105- TAT GAC CCG GAT AAC AAG GAG GAA CGC TCT AT - #C GCG ATT TAT CTA GGC 504Tyr Asp Pro Asp Asn Lys Glu Glu Arg Ser Il - #e Ala Ile Tyr Leu Gly# 120- ATA GGC TTA TGC CTT CTC TTT ATT GTG AGG AC - #A CTG CTC CTA CAC CCA 552Ile Gly Leu Cys Leu Leu Phe Ile Val Arg Th - #r Leu Leu Leu His Pro125 1 - #30 1 - #35 1 -#40- GCC ATT TTT GGC CTT CAT CAC ATT GGA ATG CA - #G ATG AGA ATA GCT ATG 600Ala Ile Phe Gly Leu His His Ile Gly Met Gl - #n Met Arg Ile Ala Met# 155- TTT AGT TTG ATT TAT AAG AAG ACT TTA AAG CT - #G TCA AGC CGT GTT CTA 648Phe Ser Leu Ile Tyr Lys Lys Thr Leu Lys Le - #u Ser Ser Arg Val Leu# 170- GAT AAA ATA AGT ATT GGA CAA CTT GTT AGT CT - #C CTT TCC AAC AAC CTG 696Asp Lys Ile Ser Ile Gly Gln Leu Val Ser Le - #u Leu Ser Asn Asn Leu# 185- AAC AAA TTT GAT GAA GGA CTT GCA TTG GCA CA - #T TTC GTG TGG ATC GCT 744Asn Lys Phe Asp Glu Gly Leu Ala Leu Ala Hi - #s Phe Val Trp Ile Ala# 200- CCT TTG CAA GTG GCA CTC CTC ATG GGG CTA AT - #C TGG GAG TTG TTA CAG 792Pro Leu Gln Val Ala Leu Leu Met Gly Leu Il - #e Trp Glu Leu Leu Gln205 2 - #10 2 - #15 2 -#20- GCG TCT GCC TTC TGT GGA CTT GGT TTC CTG AT - #A GTC CTT GCC CTT TTT 840Ala Ser Ala Phe Cys Gly Leu Gly Phe Leu Il - #e Val Leu Ala Leu Phe# 235- CAG GCT GGG CTA GGG AGA ATG ATG ATG AAG TA - #C AGA GAT CAG AGA GCT 888Gln Ala Gly Leu Gly Arg Met Met Met Lys Ty - #r Arg Asp Gln Arg Ala# 250- GGG AAG ATC AGT GAA AGA CTT GTG ATT ACC TC - #A GAA ATG ATT GAA AAT 936Gly Lys Ile Ser Glu Arg Leu Val Ile Thr Se - #r Glu Met Ile Glu Asn# 265- ATC CAA TCT GTT AAG GCA TAC TGC TGG GAA GA - #A GCA ATG GAA AAA ATG 984Ile Gln Ser Val Lys Ala Tyr Cys Trp Glu Gl - #u Ala Met Glu Lys Met# 280- ATT GAA AAC TTA AGA CAA ACA GAA CTG AAA CT - #G ACT CGG AAG GCA GCC1032Ile Glu Asn Leu Arg Gln Thr Glu Leu Lys Le - #u Thr Arg Lys Ala Ala285 2 - #90 2 - #95 3 -#00- TAT GTG AGA TAC TTC AAT AGC TCA GCC TTC TT - #C TTC TCA GGG TTC TTT1080Tyr Val Arg Tyr Phe Asn Ser Ser Ala Phe Ph - #e Phe Ser Gly Phe Phe# 315- GTG GTG TTT TTA TCT GTG CTT CCC TAT GCA CT - #A ATC AAA GGA ATC ATC1128Val Val Phe Leu Ser Val Leu Pro Tyr Ala Le - #u Ile Lys Gly Ile Ile# 330- CTC CGG AAA ATA TTC ACC ACC ATC TCA TTC TG - #C ATT GTT CTG CGC ATG1176Leu Arg Lys Ile Phe Thr Thr Ile Ser Phe Cy - #s Ile Val Leu Arg Met# 345- GCG GTC ACT CGG CAA TTT CCC TGG GCT GTA CA - #A ACA TGG TAT GAC TCT1224Ala Val Thr Arg Gln Phe Pro Trp Ala Val Gl - #n Thr Trp Tyr Asp Ser# 360- CTT GGA GCA ATA AAC AAA ATA CAG GAT TTC TT - #A CAA AAG CAA GAA TAT1272Leu Gly Ala Ile Asn Lys Ile Gln Asp Phe Le - #u Gln Lys Gln Glu Tyr365 3 - #70 3 - #75 3 -#80- AAG ACA TTG GAA TAT AAC TTA ACG ACT ACA GA - #A GTA GTG ATG GAG AAT1320Lys Thr Leu Glu Tyr Asn Leu Thr Thr Thr Gl - #u Val Val Met Glu Asn# 395- GTA ACA GCC TTC TGG GAG GAG GGA TTT GGG GA - #A TTA TTT GAG AAA GCA1368Val Thr Ala Phe Trp Glu Glu Gly Phe Gly Gl - #u Leu Phe Glu Lys Ala# 410- AAA CAA AAC AAT AAC AAT AGA AAA ACT TCT AA - #T GGT GAT GAC AGC CTC1416Lys Gln Asn Asn Asn Asn Arg Lys Thr Ser As - #n Gly Asp Asp Ser Leu# 425- TTC TTC AGT AAT TTC TCA CTT CTT GGT ACT CC - #T GTC CTG AAA GAT ATT1464Phe Phe Ser Asn Phe Ser Leu Leu Gly Thr Pr - #o Val Leu Lys Asp Ile# 440- AAT TTC AAG ATA GAA AGA GGA CAG TTG TTG GC - #G GTT GCT GGA TCC ACT1512Asn Phe Lys Ile Glu Arg Gly Gln Leu Leu Al - #a Val Ala Gly Ser Thr445 4 - #50 4 - #55 4 -#60- GGA GCA GGC AAG ACT TCA CTT CTA ATG ATG AT - #T ATG GGA GAA CTG GAG1560Gly Ala Gly Lys Thr Ser Leu Leu Met Met Il - #e Met Gly Glu Leu Glu# 475- CCT TCA GAG GGT AAA ATT AAG CAC AGT GGA AG - #A ATT TCA TTC TGT TCT1608Pro Ser Glu Gly Lys Ile Lys His Ser Gly Ar - #g Ile Ser Phe Cys Ser# 490- CAG TTT TCC TGG ATT ATG CCT GGC ACC ATT AA - #A GAA AAT ATC ATC TTT1656Gln Phe Ser Trp Ile Met Pro Gly Thr Ile Ly - #s Glu Asn Ile Ile Phe# 505- GGT GTT TCC TAT GAT GAA TAT AGA TAC AGA AG - #C GTC ATC AAA GCA TGC1704Gly Val Ser Tyr Asp Glu Tyr Arg Tyr Arg Se - #r Val Ile Lys Ala Cys# 520- CAA CTA GAA GAG GAC ATC TCC AAG TTT GCA GA - #G AAA GAC AAT ATA GTT1752Gln Leu Glu Glu Asp Ile Ser Lys Phe Ala Gl - #u Lys Asp Asn Ile Val525 5 - #30 5 - #35 5 -#40- CTT GGA GAA GGT GGA ATC ACA CTG AGT GGA GG - #T CAA CGA GCA AGA ATT1800Leu Gly Glu Gly Gly Ile Thr Leu Ser Gly Gl - #y Gln Arg Ala Arg Ile# 555- TCT TTA GCA AGA GCA GTA TAC AAA GAT GCT GA - #T TTG TAT TTA TTA GAC1848Ser Leu Ala Arg Ala Val Tyr Lys Asp Ala As - #p Leu Tyr Leu Leu Asp# 570- TCT CCT TTT GGA TAC CTA GAT GTT TTA ACA GA - #A AAA GAA ATA TTT GAA1896Ser Pro Phe Gly Tyr Leu Asp Val Leu Thr Gl - #u Lys Glu Ile Phe Glu# 585- AGC TGT GTC TGT AAA CTG ATG GCT AAC AAA AC - #T AGG ATT TTG GTC ACT1944Ser Cys Val Cys Lys Leu Met Ala Asn Lys Th - #r Arg Ile Leu Val Thr# 600- TCT AAA ATG GAA CAT TTA AAG AAA GCT GAC AA - #A ATA TTA ATT TTG AAT1992Ser Lys Met Glu His Leu Lys Lys Ala Asp Ly - #s Ile Leu Ile Leu Asn605 6 - #10 6 - #15 6 -#20- GAA GGT AGC AGC TAT TTT TAT GGG ACA TTT TC - #A GAA CTC CAA AAT CTA2040Glu Gly Ser Ser Tyr Phe Tyr Gly Thr Phe Se - #r Glu Leu Gln Asn Leu# 635- CAG CCA GAC TTT AGC TCA AAA CTC ATG GGA TG - #T GAT TCT TTC GAC CAA2088Gln Pro Asp Phe Ser Ser Lys Leu Met Gly Cy - #s Asp Ser Phe Asp Gln# 650- TTT AGT GCA GAA AGA AGA AAT TCA ATC CTA AC - #T GAG ACC TTA CAC CGT2136Phe Ser Ala Glu Arg Arg Asn Ser Ile Leu Th - #r Glu Thr Leu His Arg# 665- TTC TCA TTA GAA GGA GAT GCT CCT GTC TCC TG - #G ACA GAA ACA AAA AAA2184Phe Ser Leu Glu Gly Asp Ala Pro Val Ser Tr - #p Thr Glu Thr Lys Lys# 680- CAA TCT TTT AAA CAG ACT GGA GAG TTT GGG GA - #A AAA AGG AAG AAT TCT2232Gln Ser Phe Lys Gln Thr Gly Glu Phe Gly Gl - #u Lys Arg Lys Asn Ser685 6 - #90 6 - #95 7 -#00- ATT CTC AAT CCA ATC AAC TCT ATA CGA AAA TT - #T TCC ATT GTG CAA AAG2280Ile Leu Asn Pro Ile Asn Ser Ile Arg Lys Ph - #e Ser Ile Val Gln Lys# 715- ACT CCC TTA CAA ATG AAT GGC ATC GAA GAG GA - #T TCT GAT GAG CCT TTA2328Thr Pro Leu Gln Met Asn Gly Ile Glu Glu As - #p Ser Asp Glu Pro Leu# 730- GAG AGA AGG CTG TCC TTA GTA CCA GAT TCT GA - #G CAG GGA GAG GCG ATA2376Glu Arg Arg Leu Ser Leu Val Pro Asp Ser Gl - #u Gln Gly Glu Ala Ile# 745- CTG CCT CGC ATC AGC GTG ATC AGC ACT GGC CC - #C ACG CTT CAG GCA CGA2424Leu Pro Arg Ile Ser Val Ile Ser Thr Gly Pr - #o Thr Leu Gln Ala Arg# 760- AGG AGG CAG TCT GTC CTG AAC CTG ATG ACA CA - #C TCA GTT AAC CAA GGT2472Arg Arg Gln Ser Val Leu Asn Leu Met Thr Hi - #s Ser Val Asn Gln Gly765 7 - #70 7 - #75 7 -#80- CAG AAC ATT CAC CGA AAG ACA ACA GCA TCC AC - #A CGA AAA GTG TCA CTG2520Gln Asn Ile His Arg Lys Thr Thr Ala Ser Th - #r Arg Lys Val Ser Leu# 795- GCC CCT CAG GCA AAC TTG ACT GAA CTG GAT AT - #A TAT TCA AGA AGG TTA2568Ala Pro Gln Ala Asn Leu Thr Glu Leu Asp Il - #e Tyr Ser Arg Arg Leu# 810- TCT CAA GAA ACT GGC TTG GAA ATA AGT GAA GA - #A ATT AAC GAA GAA GAC2616Ser Gln Glu Thr Gly Leu Glu Ile Ser Glu Gl - #u Ile Asn Glu Glu Asp# 825- TTA AAG GAG TGC CTT TTT GAT GAT ATG GAG AG - #C ATA CCA GCA GTG ACT2664Leu Lys Glu Cys Leu Phe Asp Asp Met Glu Se - #r Ile Pro Ala Val Thr# 840- ACA TGG AAC ACA TAC CTT CGA TAT ATT ACT GT - #C CAC AAG AGC TTA ATT2712Thr Trp Asn Thr Tyr Leu Arg Tyr Ile Thr Va - #l His Lys Ser Leu Ile845 8 - #50 8 - #55 8 -#60- TTT GTG CTA ATT TGG TGC TTA GTA ATT TTT CT - #G GCA GAG GTG GCT GCT2760Phe Val Leu Ile Trp Cys Leu Val Ile Phe Le - #u Ala Glu Val Ala Ala# 875- TCT TTG GTT GTG CTG TGG CTC CTT GGA AAC AC - #T CCT CTT CAA GAC AAA2808Ser Leu Val Val Leu Trp Leu Leu Gly Asn Th - #r Pro Leu Gln Asp Lys# 890- GGG AAT AGT ACT CAT AGT AGA AAT AAC AGC TA - #T GCA GTG ATT ATC ACC2856Gly Asn Ser Thr His Ser Arg Asn Asn Ser Ty - #r Ala Val Ile Ile Thr# 905- AGC ACC AGT TCG TAT TAT GTG TTT TAC ATT TA - #C GTG GGA GTA GCC GAC2904Ser Thr Ser Ser Tyr Tyr Val Phe Tyr Ile Ty - #r Val Gly Val Ala Asp# 920- ACT TTG CTT GCT ATG GGA TTC TTC AGA GGT CT - #A CCA CTG GTG CAT ACT2952Thr Leu Leu Ala Met Gly Phe Phe Arg Gly Le - #u Pro Leu Val His Thr925 9 - #30 9 - #35 9 -#40- CTA ATC ACA GTG TCG AAA ATT TTA CAC CAC AA - #A ATG TTA CAT TCT GTT3000Leu Ile Thr Val Ser Lys Ile Leu His His Ly - #s Met Leu His Ser Val# 955- CTT CAA GCA CCT ATG TCA ACC CTC AAC ACG TT - #G AAA GCA GGT GGG ATT3048Leu Gln Ala Pro Met Ser Thr Leu Asn Thr Le - #u Lys Ala Gly Gly Ile# 970- CTT AAT AGA TTC TCC AAA GAT ATA GCA ATT TT - #G GAT GAC CTT CTG CCT3096Leu Asn Arg Phe Ser Lys Asp Ile Ala Ile Le - #u Asp Asp Leu Leu Pro# 985- CTT ACC ATA TTT GAC TTC ATC CAG TTG TTA TT - #A ATT GTG ATT GGA GCT3144Leu Thr Ile Phe Asp Phe Ile Gln Leu Leu Le - #u Ile Val Ile Gly Ala# 1000- ATA GCA GTT GTC GCA GTT TTA CAA CCC TAC AT - #C TTT GTT GCA ACA GTG3192Ile Ala Val Val Ala Val Leu Gln Pro Tyr Il - #e Phe Val Ala Thr Val# 10201010 - # 1015- CCA GTG ATA GTG GCT TTT ATT ATG TTG AGA GC - #A TAT TTC CTC CAA ACC3240Pro Val Ile Val Ala Phe Ile Met Leu Arg Al - #a Tyr Phe Leu Gln Thr# 10350- TCA CAG CAA CTC AAA CAA CTG GAA TCT GAA GG - #C AGG AGT CCA ATT TTC3288Ser Gln Gln Leu Lys Gln Leu Glu Ser Glu Gl - #y Arg Ser Pro Ile Phe# 10505- ACT CAT CTT GTT ACA AGC TTA AAA GGA CTA TG - #G ACA CTT CGT GCC TTC3336Thr His Leu Val Thr Ser Leu Lys Gly Leu Tr - #p Thr Leu Arg Ala Phe# 10650- GGA CGG CAG CCT TAC TTT GAA ACT CTG TTC CA - #C AAA GCT CTG AAT TTA3384Gly Arg Gln Pro Tyr Phe Glu Thr Leu Phe Hi - #s Lys Ala Leu Asn Leu# 10805- CAT ACT GCC AAC TGG TTC TTG TAC CTG TCA AC - #A CTG CGC TGG TTC CAA3432His Thr Ala Asn Trp Phe Leu Tyr Leu Ser Th - #r Leu Arg Trp Phe Gln# 11001090 - # 1095- ATG AGA ATA GAA ATG ATT TTT GTC ATC TTC TT - #C ATT GCT GTT ACC TTC3480Met Arg Ile Glu Met Ile Phe Val Ile Phe Ph - #e Ile Ala Val Thr Phe# 11150- ATT TCC ATT TTA ACA ACA GGA GAA GGA GAA GG - #A AGA GTT GGT ATT ATC3528Ile Ser Ile Leu Thr Thr Gly Glu Gly Glu Gl - #y Arg Val Gly Ile Ile# 11305- CTG ACT TTA GCC ATG AAT ATC ATG AGT ACA TT - #G CAG TGG GCT GTA AAC3576Leu Thr Leu Ala Met Asn Ile Met Ser Thr Le - #u Gln Trp Ala Val Asn# 11450- TCC AGC ATA GAT GTG GAT AGC TTG ATG CGA TC - #T GTG AGC CGA GTC TTT3624Ser Ser Ile Asp Val Asp Ser Leu Met Arg Se - #r Val Ser Arg Val Phe# 11605- AAG TTC ATT GAC ATG CCA ACA GAA GGT AAA CC - #T ACC AAG TCA ACC AAA3672Lys Phe Ile Asp Met Pro Thr Glu Gly Lys Pr - #o Thr Lys Ser Thr Lys# 11801170 - # 1175- CCA TAC AAG AAT GGC CAA CTC TCG AAA GTT AT - #G ATT ATT GAG AAT TCA3720Pro Tyr Lys Asn Gly Gln Leu Ser Lys Val Me - #t Ile Ile Glu Asn Ser# 11950- CAC GTG AAG AAA GAT GAC ATC TGG CCC TCA GG - #G GGC CAA ATG ACT GTC3768His Val Lys Lys Asp Asp Ile Trp Pro Ser Gl - #y Gly Gln Met Thr Val# 12105- AAA GAT CTC ACA GCA AAA TAC ACA GAA GGT GG - #A AAT GCC ATA TTA GAG3816Lys Asp Leu Thr Ala Lys Tyr Thr Glu Gly Gl - #y Asn Ala Ile Leu Glu# 12250- AAC ATT TCC TTC TCA ATA AGT CCT GGC CAG AG - #G GTG GGC CTC TTG GGA3864Asn Ile Ser Phe Ser Ile Ser Pro Gly Gln Ar - #g Val Gly Leu Leu Gly# 12405- AGA ACT GGA TCA GGG AAG AGT ACT TTG TTA TC - #A GCT TTT TTG AGA CTA3912Arg Thr Gly Ser Gly Lys Ser Thr Leu Leu Se - #r Ala Phe Leu Arg Leu# 12601250 - # 1255- CTG AAC ACT GAA GGA GAA ATC CAG ATC GAT GG - #T GTG TCT TGG GAT TCA3960Leu Asn Thr Glu Gly Glu Ile Gln Ile Asp Gl - #y Val Ser Trp Asp Ser# 12750- ATA ACT TTG CAA CAG TGG AGG AAA GCC TTT GG - #A GTG ATA CCA CAG AAA4008Ile Thr Leu Gln Gln Trp Arg Lys Ala Phe Gl - #y Val Ile Pro Gln Lys# 12905- GTA TTT ATT TTT TCT GGA ACA TTT AGA AAA AA - #C TTG GAT CCC TAT GAA4056Val Phe Ile Phe Ser Gly Thr Phe Arg Lys As - #n Leu Asp Pro Tyr Glu# 13050- CAG TGG AGT GAT CAA GAA ATA TGG AAA GTT GC - #A GAT GAG GTT GGG CTC4104Gln Trp Ser Asp Gln Glu Ile Trp Lys Val Al - #a Asp Glu Val Gly Leu# 13205- AGA TCT GTG ATA GAA CAG TTT CCT GGG AAG CT - #T GAC TTT GTC CTT GTG4152Arg Ser Val Ile Glu Gln Phe Pro Gly Lys Le - #u Asp Phe Val Leu Val# 13401330 - # 1335- GAT GGG GGC TGT GTC CTA AGC CAT GGC CAC AA - #G CAG TTG ATG TGC TTG4200Asp Gly Gly Cys Val Leu Ser His Gly His Ly - #s Gln Leu Met Cys Leu# 13550- GCT AGA TCT GTT CTC AGT AAG GCG AAG ATC TT - #G CTG CTT GAT GAA CCC4248Ala Arg Ser Val Leu Ser Lys Ala Lys Ile Le - #u Leu Leu Asp Glu Pro# 13705- AGT GCT CAT TTG GAT CCA GTA ACA TAC CAA AT - #A ATT AGA AGA ACT CTA4296Ser Ala His Leu Asp Pro Val Thr Tyr Gln Il - #e Ile Arg Arg Thr Leu# 13850- AAA CAA GCA TTT GCT GAT TGC ACA GTA ATT CT - #C TGT GAA CAC AGG ATA4344Lys Gln Ala Phe Ala Asp Cys Thr Val Ile Le - #u Cys Glu His Arg Ile# 14005- GAA GCA ATG CTG GAA TGC CAA CAA TTT TTG GT - #C ATA GAA GAG AAC AAA4392Glu Ala Met Leu Glu Cys Gln Gln Phe Leu Va - #l Ile Glu Glu Asn Lys# 14201410 - # 1415- GTG CGG CAG TAC GAT TCC ATC CAG AAA CTG CT - #G AAC GAG AGG AGC CTC4440Val Arg Gln Tyr Asp Ser Ile Gln Lys Leu Le - #u Asn Glu Arg Ser Leu# 14350- TTC CGG CAA GCC ATC AGC CCC TCC GAC AGG GT - #G AAG CTC TTT CCC CAC4488Phe Arg Gln Ala Ile Ser Pro Ser Asp Arg Va - #l Lys Leu Phe Pro His# 14505- CGG AAC TCA AGC AAG TGC AAG TCT AAG CCC CA - #G ATT GCT GCT CTG AAA4536Arg Asn Ser Ser Lys Cys Lys Ser Lys Pro Gl - #n Ile Ala Ala Leu Lys# 14650- GAG GAG ACA GAA GAA GAG GTG CAA GAT ACA AG - #G CTT TAGAGAGCAG4582Glu Glu Thr Glu Glu Glu Val Gln Asp Thr Ar - #g Leu# 14805- CATAAATGTT GACATGGGAC ATTTGCTCAT GGAATTGGAG CTCGTGGGAC AG - #TCACCTCA4642- TGGAATTGGA GCTCGTGGAA CAGTTACCTC TGCCTCAGAA AACAAGGATG AA - #TTAAGTTT4702- TTTTTTAAAA AAGAAACATT TGGTAAGGGG AATTGAGGAC ACTGATATGG GT - #CTTGATAA4762- ATGGCTTCCT GGCAATAGTC AAATTGTGTG AAAGGTACTT CAAATCCTTG AA - #GATTTACC4822- ACTTGTGTTT TGCAAGCCAG ATTTTCCTGA AAACCCTTGC CATGTGCTAG TA - #ATTGGAAA4882- GGCAGCTCTA AATGTCAATC AGCCTAGTTG ATCAGCTTAT TGTCTAGTGA AA - #CTCGTTAA4942- TTTGTAGTGT TGGAGAAGAA CTGAAATCAT ACTTCTTAGG GTTATGATTA AG - #TAATGATA5002- ACTGGAAACT TCAGCGGTTT ATATAAGCTT GTATTCCTTT TTCTCTCCTC TC - #CCCATGAT5062- GTTTAGAAAC ACAACTATAT TGTTTGCTAA GCATTCCAAC TATCTCATTT CC - #AAGCAAGT5122- ATTAGAATAC CACAGGAACC ACAAGACTGC ACATCAAAAT ATGCCCCATT CA - #ACATCTAG5182- TGAGCAGTCA GGAAAGAGAA CTTCCAGATC CTGGAAATCA GGGTTAGTAT TG - #TCCAGGTC5242- TACCAAAAAT CTCAATATTT CAGATAATCA CAATACATCC CTTACCTGGG AA - #AGGGCTGT5302- TATAATCTTT CACAGGGGAC AGGATGGTTC CCTTGATGAA GAAGTTGATA TG - #CCTTTTCC5362- CAACTCCAGA AAGTGACAAG CTCACAGACC TTTGAACTAG AGTTTAGCTG GA - #AAAGTATG5422- TTAGTGCAAA TTGTCACAGG ACAGCCCTTC TTTCCACAGA AGCTCCAGGT AG - #AGGGTGTG5482- TAAGTAGATA GGCCATGGGC ACTGTGGGTA GACACACATG AAGTCCAAGC AT - #TTAGATGT5542- ATAGGTTGAT GGTGGTATGT TTTCAGGCTA GATGTATGTA CTTCATGCTG TC - #TACACTAA5602- GAGAGAATGA GAGACACACT GAAGAAGCAC CAATCATGAA TTAGTTTTAT AT - #GCTTCTGT5662- TTTATAATTT TGTGAAGCAA AATTTTTTCT CTAGGAAATA TTTATTTTAA TA - #ATGTTTCA5722- AACATATATT ACAATGCTGT ATTTTAAAAG AATGATTATG AATTACATTT GT - #ATAAAATA5782- ATTTTTATAT TTGAAATATT GACTTTTTAT GGCACTAGTA TTTTTATGAA AT - #ATTATGTT5842- AAAACTGGGA CAGGGGAGAA CCTAGGGTGA TATTAACCAG GGGCCATGAA TC - #ACCTTTTG5902- GTCTGGAGGG AAGCCTTGGG GCTGATCGAG TTGTTGCCCA CAGCTGTATG AT - #TCCCAGCC5962- AGACACAGCC TCTTAGATGC AGTTCTGAAG AAGATGGTAC CACCAGTCTG AC - #TGTTTCCA6022- TCAAGGGTAC ACTGCCTTCT CAACTCCAAA CTGACTCTTA AGAAGACTGC AT - #TATATTTA6082# 6129TCAC TTGTCAATAA AATCCATACA TTTGTGT- (2) INFORMATION FOR SEQ ID NO:2:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 1480 amino (B) TYPE: amino acid (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: protein- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:- Met Gln Arg Ser Pro Leu Glu Lys Ala Ser Va - #l Val Ser Lys Leu Phe# 15- Phe Ser Trp Thr Arg Pro Ile Leu Arg Lys Gl - #y Tyr Arg Gln Arg Leu# 30- Glu Leu Ser Asp Ile Tyr Gln Ile Pro Ser Va - #l Asp Ser Ala Asp Asn# 45- Leu Ser Glu Lys Leu Glu Arg Glu Trp Asp Ar - #g Glu Leu Ala Ser Lys# 60- Lys Asn Pro Lys Leu Ile Asn Ala Leu Arg Ar - #g Cys Phe Phe Trp Arg# 80- Phe Met Phe Tyr Gly Ile Phe Leu Tyr Leu Gl - #y Glu Val Thr Lys Ala# 95- Val Gln Pro Leu Leu Leu Gly Arg Ile Ile Al - #a Ser Tyr Asp Pro Asp# 110- Asn Lys Glu Glu Arg Ser Ile Ala Ile Tyr Le - #u Gly Ile Gly Leu Cys# 125- Leu Leu Phe Ile Val Arg Thr Leu Leu Leu Hi - #s Pro Ala Ile Phe Gly# 140- Leu His His Ile Gly Met Gln Met Arg Ile Al - #a Met Phe Ser Leu Ile145 1 - #50 1 - #55 1 -#60- Tyr Lys Lys Thr Leu Lys Leu Ser Ser Arg Va - #l Leu Asp Lys Ile Ser# 175- Ile Gly Gln Leu Val Ser Leu Leu Ser Asn As - #n Leu Asn Lys Phe Asp# 190- Glu Gly Leu Ala Leu Ala His Phe Val Trp Il - #e Ala Pro Leu Gln Val# 205- Ala Leu Leu Met Gly Leu Ile Trp Glu Leu Le - #u Gln Ala Ser Ala Phe# 220- Cys Gly Leu Gly Phe Leu Ile Val Leu Ala Le - #u Phe Gln Ala Gly Leu225 2 - #30 2 - #35 2 -#40- Gly Arg Met Met Met Lys Tyr Arg Asp Gln Ar - #g Ala Gly Lys Ile Ser# 255- Glu Arg Leu Val Ile Thr Ser Glu Met Ile Gl - #u Asn Ile Gln Ser Val# 270- Lys Ala Tyr Cys Trp Glu Glu Ala Met Glu Ly - #s Met Ile Glu Asn Leu# 285- Arg Gln Thr Glu Leu Lys Leu Thr Arg Lys Al - #a Ala Tyr Val Arg Tyr# 300- Phe Asn Ser Ser Ala Phe Phe Phe Ser Gly Ph - #e Phe Val Val Phe Leu305 3 - #10 3 - #15 3 -#20- Ser Val Leu Pro Tyr Ala Leu Ile Lys Gly Il - #e Ile Leu Arg Lys Ile# 335- Phe Thr Thr Ile Ser Phe Cys Ile Val Leu Ar - #g Met Ala Val Thr Arg# 350- Gln Phe Pro Trp Ala Val Gln Thr Trp Tyr As - #p Ser Leu Gly Ala Ile# 365- Asn Lys Ile Gln Asp Phe Leu Gln Lys Gln Gl - #u Tyr Lys Thr Leu Glu# 380- Tyr Asn Leu Thr Thr Thr Glu Val Val Met Gl - #u Asn Val Thr Ala Phe385 3 - #90 3 - #95 4 -#00- Trp Glu Glu Gly Phe Gly Glu Leu Phe Glu Ly - #s Ala Lys Gln Asn Asn# 415- Asn Asn Arg Lys Thr Ser Asn Gly Asp Asp Se - #r Leu Phe Phe Ser Asn# 430- Phe Ser Leu Leu Gly Thr Pro Val Leu Lys As - #p Ile Asn Phe Lys Ile# 445- Glu Arg Gly Gln Leu Leu Ala Val Ala Gly Se - #r Thr Gly Ala Gly Lys# 460- Thr Ser Leu Leu Met Met Ile Met Gly Glu Le - #u Glu Pro Ser Glu Gly465 4 - #70 4 - #75 4 -#80- Lys Ile Lys His Ser Gly Arg Ile Ser Phe Cy - #s Ser Gln Phe Ser Trp# 495- Ile Met Pro Gly Thr Ile Lys Glu Asn Ile Il - #e Phe Gly Val Ser Tyr# 510- Asp Glu Tyr Arg Tyr Arg Ser Val Ile Lys Al - #a Cys Gln Leu Glu Glu# 525- Asp Ile Ser Lys Phe Ala Glu Lys Asp Asn Il - #e Val Leu Gly Glu Gly# 540- Gly Ile Thr Leu Ser Gly Gly Gln Arg Ala Ar - #g Ile Ser Leu Ala Arg545 5 - #50 5 - #55 5 -#60- Ala Val Tyr Lys Asp Ala Asp Leu Tyr Leu Le - #u Asp Ser Pro Phe Gly# 575- Tyr Leu Asp Val Leu Thr Glu Lys Glu Ile Ph - #e Glu Ser Cys Val Cys# 590- Lys Leu Met Ala Asn Lys Thr Arg Ile Leu Va - #l Thr Ser Lys Met Glu# 605- His Leu Lys Lys Ala Asp Lys Ile Leu Ile Le - #u Asn Glu Gly Ser Ser# 620- Tyr Phe Tyr Gly Thr Phe Ser Glu Leu Gln As - #n Leu Gln Pro Asp Phe625 6 - #30 6 - #35 6 -#40- Ser Ser Lys Leu Met Gly Cys Asp Ser Phe As - #p Gln Phe Ser Ala Glu# 655- Arg Arg Asn Ser Ile Leu Thr Glu Thr Leu Hi - #s Arg Phe Ser Leu Glu# 670- Gly Asp Ala Pro Val Ser Trp Thr Glu Thr Ly - #s Lys Gln Ser Phe Lys# 685- Gln Thr Gly Glu Phe Gly Glu Lys Arg Lys As - #n Ser Ile Leu Asn Pro# 700- Ile Asn Ser Ile Arg Lys Phe Ser Ile Val Gl - #n Lys Thr Pro Leu Gln705 7 - #10 7 - #15 7 -#20- Met Asn Gly Ile Glu Glu Asp Ser Asp Glu Pr - #o Leu Glu Arg Arg Leu# 735- Ser Leu Val Pro Asp Ser Glu Gln Gly Glu Al - #a Ile Leu Pro Arg Ile# 750- Ser Val Ile Ser Thr Gly Pro Thr Leu Gln Al - #a Arg Arg Arg Gln Ser# 765- Val Leu Asn Leu Met Thr His Ser Val Asn Gl - #n Gly Gln Asn Ile His# 780- Arg Lys Thr Thr Ala Ser Thr Arg Lys Val Se - #r Leu Ala Pro Gln Ala785 7 - #90 7 - #95 8 -#00- Asn Leu Thr Glu Leu Asp Ile Tyr Ser Arg Ar - #g Leu Ser Gln Glu Thr# 815- Gly Leu Glu Ile Ser Glu Glu Ile Asn Glu Gl - #u Asp Leu Lys Glu Cys# 830- Leu Phe Asp Asp Met Glu Ser Ile Pro Ala Va - #l Thr Thr Trp Asn Thr# 845- Tyr Leu Arg Tyr Ile Thr Val His Lys Ser Le - #u Ile Phe Val Leu Ile# 860- Trp Cys Leu Val Ile Phe Leu Ala Glu Val Al - #a Ala Ser Leu Val Val865 8 - #70 8 - #75 8 -#80- Leu Trp Leu Leu Gly Asn Thr Pro Leu Gln As - #p Lys Gly Asn Ser Thr# 895- His Ser Arg Asn Asn Ser Tyr Ala Val Ile Il - #e Thr Ser Thr Ser Ser# 910- Tyr Tyr Val Phe Tyr Ile Tyr Val Gly Val Al - #a Asp Thr Leu Leu Ala# 925- Met Gly Phe Phe Arg Gly Leu Pro Leu Val Hi - #s Thr Leu Ile Thr Val# 940- Ser Lys Ile Leu His His Lys Met Leu His Se - #r Val Leu Gln Ala Pro945 9 - #50 9 - #55 9 -#60- Met Ser Thr Leu Asn Thr Leu Lys Ala Gly Gl - #y Ile Leu Asn Arg Phe# 975- Ser Lys Asp Ile Ala Ile Leu Asp Asp Leu Le - #u Pro Leu Thr Ile Phe# 990- Asp Phe Ile Gln Leu Leu Leu Ile Val Ile Gl - #y Ala Ile Ala Val Val# 10050- Ala Val Leu Gln Pro Tyr Ile Phe Val Ala Th - #r Val Pro Val Ile Val# 10205- Ala Phe Ile Met Leu Arg Ala Tyr Phe Leu Gl - #n Thr Ser Gln Gln Leu# 10401030 - # 1035- Lys Gln Leu Glu Ser Glu Gly Arg Ser Pro Il - #e Phe Thr His Leu Val# 10550- Thr Ser Leu Lys Gly Leu Trp Thr Leu Arg Al - #a Phe Gly Arg Gln Pro# 10705- Tyr Phe Glu Thr Leu Phe His Lys Ala Leu As - #n Leu His Thr Ala Asn# 10850- Trp Phe Leu Tyr Leu Ser Thr Leu Arg Trp Ph - #e Gln Met Arg Ile Glu# 11005- Met Ile Phe Val Ile Phe Phe Ile Ala Val Th - #r Phe Ile Ser Ile Leu# 11201110 - # 1115- Thr Thr Gly Glu Gly Glu Gly Arg Val Gly Il - #e Ile Leu Thr Leu Ala# 11350- Met Asn Ile Met Ser Thr Leu Gln Trp Ala Va - #l Asn Ser Ser Ile Asp# 11505- Val Asp Ser Leu Met Arg Ser Val Ser Arg Va - #l Phe Lys Phe Ile Asp# 11650- Met Pro Thr Glu Gly Lys Pro Thr Lys Ser Th - #r Lys Pro Tyr Lys Asn# 11805- Gly Gln Leu Ser Lys Val Met Ile Ile Glu As - #n Ser His Val Lys Lys# 12001190 - # 1195- Asp Asp Ile Trp Pro Ser Gly Gly Gln Met Th - #r Val Lys Asp Leu Thr# 12150- Ala Lys Tyr Thr Glu Gly Gly Asn Ala Ile Le - #u Glu Asn Ile Ser Phe# 12305- Ser Ile Ser Pro Gly Gln Arg Val Gly Leu Le - #u Gly Arg Thr Gly Ser# 12450- Gly Lys Ser Thr Leu Leu Ser Ala Phe Leu Ar - #g Leu Leu Asn Thr Glu# 12605- Gly Glu Ile Gln Ile Asp Gly Val Ser Trp As - #p Ser Ile Thr Leu Gln# 12801270 - # 1275- Gln Trp Arg Lys Ala Phe Gly Val Ile Pro Gl - #n Lys Val Phe Ile Phe# 12950- Ser Gly Thr Phe Arg Lys Asn Leu Asp Pro Ty - #r Glu Gln Trp Ser Asp# 13105- Gln Glu Ile Trp Lys Val Ala Asp Glu Val Gl - #y Leu Arg Ser Val Ile# 13250- Glu Gln Phe Pro Gly Lys Leu Asp Phe Val Le - #u Val Asp Gly Gly Cys# 13405- Val Leu Ser His Gly His Lys Gln Leu Met Cy - #s Leu Ala Arg Ser Val# 13601350 - # 1355- Leu Ser Lys Ala Lys Ile Leu Leu Leu Asp Gl - #u Pro Ser Ala His Leu# 13750- Asp Pro Val Thr Tyr Gln Ile Ile Arg Arg Th - #r Leu Lys Gln Ala Phe# 13905- Ala Asp Cys Thr Val Ile Leu Cys Glu His Ar - #g Ile Glu Ala Met Leu# 14050- Glu Cys Gln Gln Phe Leu Val Ile Glu Glu As - #n Lys Val Arg Gln Tyr# 14205- Asp Ser Ile Gln Lys Leu Leu Asn Glu Arg Se - #r Leu Phe Arg Gln Ala# 14401430 - # 1435- Ile Ser Pro Ser Asp Arg Val Lys Leu Phe Pr - #o His Arg Asn Ser Ser# 14550- Lys Cys Lys Ser Lys Pro Gln Ile Ala Ala Le - #u Lys Glu Glu Thr Glu# 14705- Glu Glu Val Gln Asp Thr Arg Leu# 1480- (2) INFORMATION FOR SEQ ID NO:3:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 6126 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (ix) FEATURE: (A) NAME/KEY: CDS (B) LOCATION: 133..4569- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:- AATTGGAAGC AAATGACATC ACAGCAGGTC AGAGAAAAAG GGTTGAGCGG CA - #GGCACCCA 60- GAGTAGTAGG TCTTTGGCAT TAGGAGCTTG AGCCCAGACG GCCCTAGCAG GG - #ACCCCAGC 120- GCCCGAGAGA CC ATG CAG AGG TCG CCT CTG GAA AAG - # GCC AGC GTT GTC 168 Met Gln Ar - #g Ser Pro Leu Glu Lys Ala Ser Val Val# 10- TCC AAA CTT TTT TTC AGC TGG ACC AGA CCA AT - #T TTG AGG AAA GGA TAC 216Ser Lys Leu Phe Phe Ser Trp Thr Arg Pro Il - #e Leu Arg Lys Gly Tyr# 25- AGA CAG CGC CTG GAA TTG TCA GAC ATA TAC CA - #A ATC CCT TCT GTT GAT 264Arg Gln Arg Leu Glu Leu Ser Asp Ile Tyr Gl - #n Ile Pro Ser Val Asp# 40- TCT GCT GAC AAT CTA TCT GAA AAA TTG GAA AG - #A GAA TGG GAT AGA GAG 312Ser Ala Asp Asn Leu Ser Glu Lys Leu Glu Ar - #g Glu Trp Asp Arg Glu# 60- CTG GCT TCA AAG AAA AAT CCT AAA CTC ATT AA - #T GCC CTT CGG CGA TGT 360Leu Ala Ser Lys Lys Asn Pro Lys Leu Ile As - #n Ala Leu Arg Arg Cys# 75- TTT TTC TGG AGA TTT ATG TTC TAT GGA ATC TT - #T TTA TAT TTA GGG GAA 408Phe Phe Trp Arg Phe Met Phe Tyr Gly Ile Ph - #e Leu Tyr Leu Gly Glu# 90- GTC ACC AAA GCA GTA CAG CCT CTC TTA CTG GG - #A AGA ATC ATA GCT TCC 456Val Thr Lys Ala Val Gln Pro Leu Leu Leu Gl - #y Arg Ile Ile Ala Ser# 105- TAT GAC CCG GAT AAC AAG GAG GAA CGC TCT AT - #C GCG ATT TAT CTA GGC 504Tyr Asp Pro Asp Asn Lys Glu Glu Arg Ser Il - #e Ala Ile Tyr Leu Gly# 120- ATA GGC TTA TGC CTT CTC TTT ATT GTG AGG AC - #A CTG CTC CTA CAC CCA 552Ile Gly Leu Cys Leu Leu Phe Ile Val Arg Th - #r Leu Leu Leu His Pro125 1 - #30 1 - #35 1 -#40- GCC ATT TTT GGC CTT CAT CAC ATT GGA ATG CA - #G ATG AGA ATA GCT ATG 600Ala Ile Phe Gly Leu His His Ile Gly Met Gl - #n Met Arg Ile Ala Met# 155- TTT AGT TTG ATT TAT AAG AAG ACT TTA AAG CT - #G TCA AGC CGT GTT CTA 648Phe Ser Leu Ile Tyr Lys Lys Thr Leu Lys Le - #u Ser Ser Arg Val Leu# 170- GAT AAA ATA AGT ATT GGA CAA CTT GTT AGT CT - #C CTT TCC AAC AAC CTG 696Asp Lys Ile Ser Ile Gly Gln Leu Val Ser Le - #u Leu Ser Asn Asn Leu# 185- AAC AAA TTT GAT GAA GGA CTT GCA TTG GCA CA - #T TTC GTG TGG ATC GCT 744Asn Lys Phe Asp Glu Gly Leu Ala Leu Ala Hi - #s Phe Val Trp Ile Ala# 200- CCT TTG CAA GTG GCA CTC CTC ATG GGG CTA AT - #C TGG GAG TTG TTA CAG 792Pro Leu Gln Val Ala Leu Leu Met Gly Leu Il - #e Trp Glu Leu Leu Gln205 2 - #10 2 - #15 2 -#20- GCG TCT GCC TTC TGT GGA CTT GGT TTC CTG AT - #A GTC CTT GCC CTT TTT 840Ala Ser Ala Phe Cys Gly Leu Gly Phe Leu Il - #e Val Leu Ala Leu Phe# 235- CAG GCT GGG CTA GGG AGA ATG ATG ATG AAG TA - #C AGA GAT CAG AGA GCT 888Gln Ala Gly Leu Gly Arg Met Met Met Lys Ty - #r Arg Asp Gln Arg Ala# 250- GGG AAG ATC AGT GAA AGA CTT GTG ATT ACC TC - #A GAA ATG ATT GAA AAT 936Gly Lys Ile Ser Glu Arg Leu Val Ile Thr Se - #r Glu Met Ile Glu Asn# 265- ATC CAA TCT GTT AAG GCA TAC TGC TGG GAA GA - #A GCA ATG GAA AAA ATG 984Ile Gln Ser Val Lys Ala Tyr Cys Trp Glu Gl - #u Ala Met Glu Lys Met# 280- ATT GAA AAC TTA AGA CAA ACA GAA CTG AAA CT - #G ACT CGG AAG GCA GCC1032Ile Glu Asn Leu Arg Gln Thr Glu Leu Lys Le - #u Thr Arg Lys Ala Ala285 2 - #90 2 - #95 3 -#00- TAT GTG AGA TAC TTC AAT AGC TCA GCC TTC TT - #C TTC TCA GGG TTC TTT1080Tyr Val Arg Tyr Phe Asn Ser Ser Ala Phe Ph - #e Phe Ser Gly Phe Phe# 315- GTG GTG TTT TTA TCT GTG CTT CCC TAT GCA CT - #A ATC AAA GGA ATC ATC1128Val Val Phe Leu Ser Val Leu Pro Tyr Ala Le - #u Ile Lys Gly Ile Ile# 330- CTC CGG AAA ATA TTC ACC ACC ATC TCA TTC TG - #C ATT GTT CTG CGC ATG1176Leu Arg Lys Ile Phe Thr Thr Ile Ser Phe Cy - #s Ile Val Leu Arg Met# 345- GCG GTC ACT CGG CAA TTT CCC TGG GCT GTA CA - #A ACA TGG TAT GAC TCT1224Ala Val Thr Arg Gln Phe Pro Trp Ala Val Gl - #n Thr Trp Tyr Asp Ser# 360- CTT GGA GCA ATA AAC AAA ATA CAG GAT TTC TT - #A CAA AAG CAA GAA TAT1272Leu Gly Ala Ile Asn Lys Ile Gln Asp Phe Le - #u Gln Lys Gln Glu Tyr365 3 - #70 3 - #75 3 -#80- AAG ACA TTG GAA TAT AAC TTA ACG ACT ACA GA - #A GTA GTG ATG GAG AAT1320Lys Thr Leu Glu Tyr Asn Leu Thr Thr Thr Gl - #u Val Val Met Glu Asn# 395- GTA ACA GCC TTC TGG GAG GAG GGA TTT GGG GA - #A TTA TTT GAG AAA GCA1368Val Thr Ala Phe Trp Glu Glu Gly Phe Gly Gl - #u Leu Phe Glu Lys Ala# 410- AAA CAA AAC AAT AAC AAT AGA AAA ACT TCT AA - #T GGT GAT GAC AGC CTC1416Lys Gln Asn Asn Asn Asn Arg Lys Thr Ser As - #n Gly Asp Asp Ser Leu# 425- TTC TTC AGT AAT TTC TCA CTT CTT GGT ACT CC - #T GTC CTG AAA GAT ATT1464Phe Phe Ser Asn Phe Ser Leu Leu Gly Thr Pr - #o Val Leu Lys Asp Ile# 440- AAT TTC AAG ATA GAA AGA GGA CAG TTG TTG GC - #G GTT GCT GGA TCC ACT1512Asn Phe Lys Ile Glu Arg Gly Gln Leu Leu Al - #a Val Ala Gly Ser Thr445 4 - #50 4 - #55 4 -#60- GGA GCA GGC AAG ACT TCA CTT CTA ATG ATG AT - #T ATG GGA GAA CTG GAG1560Gly Ala Gly Lys Thr Ser Leu Leu Met Met Il - #e Met Gly Glu Leu Glu# 475- CCT TCA GAG GGT AAA ATT AAG CAC AGT GGA AG - #A ATT TCA TTC TGT TCT1608Pro Ser Glu Gly Lys Ile Lys His Ser Gly Ar - #g Ile Ser Phe Cys Ser# 490- CAG TTT TCC TGG ATT ATG CCT GGC ACC ATT AA - #A GAA AAT ATC ATC GGT1656Gln Phe Ser Trp Ile Met Pro Gly Thr Ile Ly - #s Glu Asn Ile Ile Gly# 505- GTT TCC TAT GAT GAA TAT AGA TAC AGA AGC GT - #C ATC AAA GCA TGC CAA1704Val Ser Tyr Asp Glu Tyr Arg Tyr Arg Ser Va - #l Ile Lys Ala Cys Gln# 520- CTA GAA GAG GAC ATC TCC AAG TTT GCA GAG AA - #A GAC AAT ATA GTT CTT1752Leu Glu Glu Asp Ile Ser Lys Phe Ala Glu Ly - #s Asp Asn Ile Val Leu525 5 - #30 5 - #35 5 -#40- GGA GAA GGT GGA ATC ACA CTG AGT GGA GGT CA - #A CGA GCA AGA ATT TCT1800Gly Glu Gly Gly Ile Thr Leu Ser Gly Gly Gl - #n Arg Ala Arg Ile Ser# 555- TTA GCA AGA GCA GTA TAC AAA GAT GCT GAT TT - #G TAT TTA TTA GAC TCT1848Leu Ala Arg Ala Val Tyr Lys Asp Ala Asp Le - #u Tyr Leu Leu Asp Ser# 570- CCT TTT GGA TAC CTA GAT GTT TTA ACA GAA AA - #A GAA ATA TTT GAA AGC1896Pro Phe Gly Tyr Leu Asp Val Leu Thr Glu Ly - #s Glu Ile Phe Glu Ser# 585- TGT GTC TGT AAA CTG ATG GCT AAC AAA ACT AG - #G ATT TTG GTC ACT TCT1944Cys Val Cys Lys Leu Met Ala Asn Lys Thr Ar - #g Ile Leu Val Thr Ser# 600- AAA ATG GAA CAT TTA AAG AAA GCT GAC AAA AT - #A TTA ATT TTG AAT GAA1992Lys Met Glu His Leu Lys Lys Ala Asp Lys Il - #e Leu Ile Leu Asn Glu605 6 - #10 6 - #15 6 -#20- GGT AGC AGC TAT TTT TAT GGG ACA TTT TCA GA - #A CTC CAA AAT CTA CAG2040Gly Ser Ser Tyr Phe Tyr Gly Thr Phe Ser Gl - #u Leu Gln Asn Leu Gln# 635- CCA GAC TTT AGC TCA AAA CTC ATG GGA TGT GA - #T TCT TTC GAC CAA TTT2088Pro Asp Phe Ser Ser Lys Leu Met Gly Cys As - #p Ser Phe Asp Gln Phe# 650- AGT GCA GAA AGA AGA AAT TCA ATC CTA ACT GA - #G ACC TTA CAC CGT TTC2136Ser Ala Glu Arg Arg Asn Ser Ile Leu Thr Gl - #u Thr Leu His Arg Phe# 665- TCA TTA GAA GGA GAT GCT CCT GTC TCC TGG AC - #A GAA ACA AAA AAA CAA2184Ser Leu Glu Gly Asp Ala Pro Val Ser Trp Th - #r Glu Thr Lys Lys Gln# 680- TCT TTT AAA CAG ACT GGA GAG TTT GGG GAA AA - #A AGG AAG AAT TCT ATT2232Ser Phe Lys Gln Thr Gly Glu Phe Gly Glu Ly - #s Arg Lys Asn Ser Ile685 6 - #90 6 - #95 7 -#00- CTC AAT CCA ATC AAC TCT ATA CGA AAA TTT TC - #C ATT GTG CAA AAG ACT2280Leu Asn Pro Ile Asn Ser Ile Arg Lys Phe Se - #r Ile Val Gln Lys Thr# 715- CCC TTA CAA ATG AAT GGC ATC GAA GAG GAT TC - #T GAT GAG CCT TTA GAG2328Pro Leu Gln Met Asn Gly Ile Glu Glu Asp Se - #r Asp Glu Pro Leu Glu# 730- AGA AGG CTG TCC TTA GTA CCA GAT TCT GAG CA - #G GGA GAG GCG ATA CTG2376Arg Arg Leu Ser Leu Val Pro Asp Ser Glu Gl - #n Gly Glu Ala Ile Leu# 745- CCT CGC ATC AGC GTG ATC AGC ACT GGC CCC AC - #G CTT CAG GCA CGA AGG2424Pro Arg Ile Ser Val Ile Ser Thr Gly Pro Th - #r Leu Gln Ala Arg Arg# 760- AGG CAG TCT GTC CTG AAC CTG ATG ACA CAC TC - #A GTT AAC CAA GGT CAG2472Arg Gln Ser Val Leu Asn Leu Met Thr His Se - #r Val Asn Gln Gly Gln765 7 - #70 7 - #75 7 -#80- AAC ATT CAC CGA AAG ACA ACA GCA TCC ACA CG - #A AAA GTG TCA CTG GCC2520Asn Ile His Arg Lys Thr Thr Ala Ser Thr Ar - #g Lys Val Ser Leu Ala# 795- CCT CAG GCA AAC TTG ACT GAA CTG GAT ATA TA - #T TCA AGA AGG TTA TCT2568Pro Gln Ala Asn Leu Thr Glu Leu Asp Ile Ty - #r Ser Arg Arg Leu Ser# 810- CAA GAA ACT GGC TTG GAA ATA AGT GAA GAA AT - #T AAC GAA GAA GAC TTA2616Gln Glu Thr Gly Leu Glu Ile Ser Glu Glu Il - #e Asn Glu Glu Asp Leu# 825- AAG GAG TGC CTT TTT GAT GAT ATG GAG AGC AT - #A CCA GCA GTG ACT ACA2664Lys Glu Cys Leu Phe Asp Asp Met Glu Ser Il - #e Pro Ala Val Thr Thr# 840- TGG AAC ACA TAC CTT CGA TAT ATT ACT GTC CA - #C AAG AGC TTA ATT TTT2712Trp Asn Thr Tyr Leu Arg Tyr Ile Thr Val Hi - #s Lys Ser Leu Ile Phe845 8 - #50 8 - #55 8 -#60- GTG CTA ATT TGG TGC TTA GTA ATT TTT CTG GC - #A GAG GTG GCT GCT TCT2760Val Leu Ile Trp Cys Leu Val Ile Phe Leu Al - #a Glu Val Ala Ala Ser# 875- TTG GTT GTG CTG TGG CTC CTT GGA AAC ACT CC - #T CTT CAA GAC AAA GGG2808Leu Val Val Leu Trp Leu Leu Gly Asn Thr Pr - #o Leu Gln Asp Lys Gly# 890- AAT AGT ACT CAT AGT AGA AAT AAC AGC TAT GC - #A GTG ATT ATC ACC AGC2856Asn Ser Thr His Ser Arg Asn Asn Ser Tyr Al - #a Val Ile Ile Thr Ser# 905- ACC AGT TCG TAT TAT GTG TTT TAC ATT TAC GT - #G GGA GTA GCC GAC ACT2904Thr Ser Ser Tyr Tyr Val Phe Tyr Ile Tyr Va - #l Gly Val Ala Asp Thr# 920- TTG CTT GCT ATG GGA TTC TTC AGA GGT CTA CC - #A CTG GTG CAT ACT CTA2952Leu Leu Ala Met Gly Phe Phe Arg Gly Leu Pr - #o Leu Val His Thr Leu925 9 - #30 9 - #35 9 -#40- ATC ACA GTG TCG AAA ATT TTA CAC CAC AAA AT - #G TTA CAT TCT GTT CTT3000Ile Thr Val Ser Lys Ile Leu His His Lys Me - #t Leu His Ser Val Leu# 955- CAA GCA CCT ATG TCA ACC CTC AAC ACG TTG AA - #A GCA GGT GGG ATT CTT3048Gln Ala Pro Met Ser Thr Leu Asn Thr Leu Ly - #s Ala Gly Gly Ile Leu# 970- AAT AGA TTC TCC AAA GAT ATA GCA ATT TTG GA - #T GAC CTT CTG CCT CTT3096Asn Arg Phe Ser Lys Asp Ile Ala Ile Leu As - #p Asp Leu Leu Pro Leu# 985- ACC ATA TTT GAC TTC ATC CAG TTG TTA TTA AT - #T GTG ATT GGA GCT ATA3144Thr Ile Phe Asp Phe Ile Gln Leu Leu Leu Il - #e Val Ile Gly Ala Ile# 1000- GCA GTT GTC GCA GTT TTA CAA CCC TAC ATC TT - #T GTT GCA ACA GTG CCA3192Ala Val Val Ala Val Leu Gln Pro Tyr Ile Ph - #e Val Ala Thr Val Pro# 10201010 - # 1015- GTG ATA GTG GCT TTT ATT ATG TTG AGA GCA TA - #T TTC CTC CAA ACC TCA3240Val Ile Val Ala Phe Ile Met Leu Arg Ala Ty - #r Phe Leu Gln Thr Ser# 10350- CAG CAA CTC AAA CAA CTG GAA TCT GAA GGC AG - #G AGT CCA ATT TTC ACT3288Gln Gln Leu Lys Gln Leu Glu Ser Glu Gly Ar - #g Ser Pro Ile Phe Thr# 10505- CAT CTT GTT ACA AGC TTA AAA GGA CTA TGG AC - #A CTT CGT GCC TTC GGA3336His Leu Val Thr Ser Leu Lys Gly Leu Trp Th - #r Leu Arg Ala Phe Gly# 10650- CGG CAG CCT TAC TTT GAA ACT CTG TTC CAC AA - #A GCT CTG AAT TTA CAT3384Arg Gln Pro Tyr Phe Glu Thr Leu Phe His Ly - #s Ala Leu Asn Leu His# 10805- ACT GCC AAC TGG TTC TTG TAC CTG TCA ACA CT - #G CGC TGG TTC CAA ATG3432Thr Ala Asn Trp Phe Leu Tyr Leu Ser Thr Le - #u Arg Trp Phe Gln Met# 11001090 - # 1095- AGA ATA GAA ATG ATT TTT GTC ATC TTC TTC AT - #T GCT GTT ACC TTC ATT3480Arg Ile Glu Met Ile Phe Val Ile Phe Phe Il - #e Ala Val Thr Phe Ile# 11150- TCC ATT TTA ACA ACA GGA GAA GGA GAA GGA AG - #A GTT GGT ATT ATC CTG3528Ser Ile Leu Thr Thr Gly Glu Gly Glu Gly Ar - #g Val Gly Ile Ile Leu# 11305- ACT TTA GCC ATG AAT ATC ATG AGT ACA TTG CA - #G TGG GCT GTA AAC TCC3576Thr Leu Ala Met Asn Ile Met Ser Thr Leu Gl - #n Trp Ala Val Asn Ser# 11450- AGC ATA GAT GTG GAT AGC TTG ATG CGA TCT GT - #G AGC CGA GTC TTT AAG3624Ser Ile Asp Val Asp Ser Leu Met Arg Ser Va - #l Ser Arg Val Phe Lys# 11605- TTC ATT GAC ATG CCA ACA GAA GGT AAA CCT AC - #C AAG TCA ACC AAA CCA3672Phe Ile Asp Met Pro Thr Glu Gly Lys Pro Th - #r Lys Ser Thr Lys Pro# 11801170 - # 1175- TAC AAG AAT GGC CAA CTC TCG AAA GTT ATG AT - #T ATT GAG AAT TCA CAC3720Tyr Lys Asn Gly Gln Leu Ser Lys Val Met Il - #e Ile Glu Asn Ser His# 11950- GTG AAG AAA GAT GAC ATC TGG CCC TCA GGG GG - #C CAA ATG ACT GTC AAA3768Val Lys Lys Asp Asp Ile Trp Pro Ser Gly Gl - #y Gln Met Thr Val Lys# 12105- GAT CTC ACA GCA AAA TAC ACA GAA GGT GGA AA - #T GCC ATA TTA GAG AAC3816Asp Leu Thr Ala Lys Tyr Thr Glu Gly Gly As - #n Ala Ile Leu Glu Asn# 12250- ATT TCC TTC TCA ATA AGT CCT GGC CAG AGG GT - #G GGC CTC TTG GGA AGA3864Ile Ser Phe Ser Ile Ser Pro Gly Gln Arg Va - #l Gly Leu Leu Gly Arg# 12405- ACT GGA TCA GGG AAG AGT ACT TTG TTA TCA GC - #T TTT TTG AGA CTA CTG3912Thr Gly Ser Gly Lys Ser Thr Leu Leu Ser Al - #a Phe Leu Arg Leu Leu# 12601250 - # 1255- AAC ACT GAA GGA GAA ATC CAG ATC GAT GGT GT - #G TCT TGG GAT TCA ATA3960Asn Thr Glu Gly Glu Ile Gln Ile Asp Gly Va - #l Ser Trp Asp Ser Ile# 12750- ACT TTG CAA CAG TGG AGG AAA GCC TTT GGA GT - #G ATA CCA CAG AAA GTA4008Thr Leu Gln Gln Trp Arg Lys Ala Phe Gly Va - #l Ile Pro Gln Lys Val# 12905- TTT ATT TTT TCT GGA ACA TTT AGA AAA AAC TT - #G GAT CCC TAT GAA CAG4056Phe Ile Phe Ser Gly Thr Phe Arg Lys Asn Le - #u Asp Pro Tyr Glu Gln# 13050- TGG AGT GAT CAA GAA ATA TGG AAA GTT GCA GA - #T GAG GTT GGG CTC AGA4104Trp Ser Asp Gln Glu Ile Trp Lys Val Ala As - #p Glu Val Gly Leu Arg# 13205- TCT GTG ATA GAA CAG TTT CCT GGG AAG CTT GA - #C TTT GTC CTT GTG GAT4152Ser Val Ile Glu Gln Phe Pro Gly Lys Leu As - #p Phe Val Leu Val Asp# 13401330 - # 1335- GGG GGC TGT GTC CTA AGC CAT GGC CAC AAG CA - #G TTG ATG TGC TTG GCT4200Gly Gly Cys Val Leu Ser His Gly His Lys Gl - #n Leu Met Cys Leu Ala# 13550- AGA TCT GTT CTC AGT AAG GCG AAG ATC TTG CT - #G CTT GAT GAA CCC AGT4248Arg Ser Val Leu Ser Lys Ala Lys Ile Leu Le - #u Leu Asp Glu Pro Ser# 13705- GCT CAT TTG GAT CCA GTA ACA TAC CAA ATA AT - #T AGA AGA ACT CTA AAA4296Ala His Leu Asp Pro Val Thr Tyr Gln Ile Il - #e Arg Arg Thr Leu Lys# 13850- CAA GCA TTT GCT GAT TGC ACA GTA ATT CTC TG - #T GAA CAC AGG ATA GAA4344Gln Ala Phe Ala Asp Cys Thr Val Ile Leu Cy - #s Glu His Arg Ile Glu# 14005- GCA ATG CTG GAA TGC CAA CAA TTT TTG GTC AT - #A GAA GAG AAC AAA GTG4392Ala Met Leu Glu Cys Gln Gln Phe Leu Val Il - #e Glu Glu Asn Lys Val# 14201410 - # 1415- CGG CAG TAC GAT TCC ATC CAG AAA CTG CTG AA - #C GAG AGG AGC CTC TTC4440Arg Gln Tyr Asp Ser Ile Gln Lys Leu Leu As - #n Glu Arg Ser Leu Phe# 14350- CGG CAA GCC ATC AGC CCC TCC GAC AGG GTG AA - #G CTC TTT CCC CAC CGG4488Arg Gln Ala Ile Ser Pro Ser Asp Arg Val Ly - #s Leu Phe Pro His Arg# 14505- AAC TCA AGC AAG TGC AAG TCT AAG CCC CAG AT - #T GCT GCT CTG AAA GAG4536Asn Ser Ser Lys Cys Lys Ser Lys Pro Gln Il - #e Ala Ala Leu Lys Glu# 14650- GAG ACA GAA GAA GAG GTG CAA GAT ACA AGG CT - #T TAGAGAGCAG CATAAATGTT4589Glu Thr Glu Glu Glu Val Gln Asp Thr Arg Le - #u# 1475- GACATGGGAC ATTTGCTCAT GGAATTGGAG CTCGTGGGAC AGTCACCTCA TG - #GAATTGGA4649- GCTCGTGGAA CAGTTACCTC TGCCTCAGAA AACAAGGATG AATTAAGTTT TT - #TTTTAAAA4709- AAGAAACATT TGGTAAGGGG AATTGAGGAC ACTGATATGG GTCTTGATAA AT - #GGCTTCCT4769- GGCAATAGTC AAATTGTGTG AAAGGTACTT CAAATCCTTG AAGATTTACC AC - #TTGTGTTT4829- TGCAAGCCAG ATTTTCCTGA AAACCCTTGC CATGTGCTAG TAATTGGAAA GG - #CAGCTCTA4889- AATGTCAATC AGCCTAGTTG ATCAGCTTAT TGTCTAGTGA AACTCGTTAA TT - #TGTAGTGT4949- TGGAGAAGAA CTGAAATCAT ACTTCTTAGG GTTATGATTA AGTAATGATA AC - #TGGAAACT5009- TCAGCGGTTT ATATAAGCTT GTATTCCTTT TTCTCTCCTC TCCCCATGAT GT - #TTAGAAAC5069- ACAACTATAT TGTTTGCTAA GCATTCCAAC TATCTCATTT CCAAGCAAGT AT - #TAGAATAC5129- CACAGGAACC ACAAGACTGC ACATCAAAAT ATGCCCCATT CAACATCTAG TG - #AGCAGTCA5189- GGAAAGAGAA CTTCCAGATC CTGGAAATCA GGGTTAGTAT TGTCCAGGTC TA - #CCAAAAAT5249- CTCAATATTT CAGATAATCA CAATACATCC CTTACCTGGG AAAGGGCTGT TA - #TAATCTTT5309- CACAGGGGAC AGGATGGTTC CCTTGATGAA GAAGTTGATA TGCCTTTTCC CA - #ACTCCAGA5369- AAGTGACAAG CTCACAGACC TTTGAACTAG AGTTTAGCTG GAAAAGTATG TT - #AGTGCAAA5429- TTGTCACAGG ACAGCCCTTC TTTCCACAGA AGCTCCAGGT AGAGGGTGTG TA - #AGTAGATA5489- GGCCATGGGC ACTGTGGGTA GACACACATG AAGTCCAAGC ATTTAGATGT AT - #AGGTTGAT5549- GGTGGTATGT TTTCAGGCTA GATGTATGTA CTTCATGCTG TCTACACTAA GA - #GAGAATGA5609- GAGACACACT GAAGAAGCAC CAATCATGAA TTAGTTTTAT ATGCTTCTGT TT - #TATAATTT5669- TGTGAAGCAA AATTTTTTCT CTAGGAAATA TTTATTTTAA TAATGTTTCA AA - #CATATATT5729- ACAATGCTGT ATTTTAAAAG AATGATTATG AATTACATTT GTATAAAATA AT - #TTTTATAT5789- TTGAAATATT GACTTTTTAT GGCACTAGTA TTTTTATGAA ATATTATGTT AA - #AACTGGGA5849- CAGGGGAGAA CCTAGGGTGA TATTAACCAG GGGCCATGAA TCACCTTTTG GT - #CTGGAGGG5909- AAGCCTTGGG GCTGATCGAG TTGTTGCCCA CAGCTGTATG ATTCCCAGCC AG - #ACACAGCC5969- TCTTAGATGC AGTTCTGAAG AAGATGGTAC CACCAGTCTG ACTGTTTCCA TC - #AAGGGTAC6029- ACTGCCTTCT CAACTCCAAA CTGACTCTTA AGAAGACTGC ATTATATTTA TT - #ACTGTAAG6089# 6126 ATAA AATCCATACA TTTGTGT- (2) INFORMATION FOR SEQ ID NO:4:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 1479 amino (B) TYPE: amino acid (D) TOPOLOGY: linear- (ii) MOLECULE TYPE: protein- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:- Met Gln Arg Ser Pro Leu Glu Lys Ala Ser Va - #l Val Ser Lys Leu Phe# 15- Phe Ser Trp Thr Arg Pro Ile Leu Arg Lys Gl - #y Tyr Arg Gln Arg Leu# 30- Glu Leu Ser Asp Ile Tyr Gln Ile Pro Ser Va - #l Asp Ser Ala Asp Asn# 45- Leu Ser Glu Lys Leu Glu Arg Glu Trp Asp Ar - #g Glu Leu Ala Ser Lys# 60- Lys Asn Pro Lys Leu Ile Asn Ala Leu Arg Ar - #g Cys Phe Phe Trp Arg# 80- Phe Met Phe Tyr Gly Ile Phe Leu Tyr Leu Gl - #y Glu Val Thr Lys Ala# 95- Val Gln Pro Leu Leu Leu Gly Arg Ile Ile Al - #a Ser Tyr Asp Pro Asp# 110- Asn Lys Glu Glu Arg Ser Ile Ala Ile Tyr Le - #u Gly Ile Gly Leu Cys# 125- Leu Leu Phe Ile Val Arg Thr Leu Leu Leu Hi - #s Pro Ala Ile Phe Gly# 140- Leu His His Ile Gly Met Gln Met Arg Ile Al - #a Met Phe Ser Leu Ile145 1 - #50 1 - #55 1 -#60- Tyr Lys Lys Thr Leu Lys Leu Ser Ser Arg Va - #l Leu Asp Lys Ile Ser# 175- Ile Gly Gln Leu Val Ser Leu Leu Ser Asn As - #n Leu Asn Lys Phe Asp# 190- Glu Gly Leu Ala Leu Ala His Phe Val Trp Il - #e Ala Pro Leu Gln Val# 205- Ala Leu Leu Met Gly Leu Ile Trp Glu Leu Le - #u Gln Ala Ser Ala Phe# 220- Cys Gly Leu Gly Phe Leu Ile Val Leu Ala Le - #u Phe Gln Ala Gly Leu225 2 - #30 2 - #35 2 -#40- Gly Arg Met Met Met Lys Tyr Arg Asp Gln Ar - #g Ala Gly Lys Ile Ser# 255- Glu Arg Leu Val Ile Thr Ser Glu Met Ile Gl - #u Asn Ile Gln Ser Val# 270- Lys Ala Tyr Cys Trp Glu Glu Ala Met Glu Ly - #s Met Ile Glu Asn Leu# 285- Arg Gln Thr Glu Leu Lys Leu Thr Arg Lys Al - #a Ala Tyr Val Arg Tyr# 300- Phe Asn Ser Ser Ala Phe Phe Phe Ser Gly Ph - #e Phe Val Val Phe Leu305 3 - #10 3 - #15 3 -#20- Ser Val Leu Pro Tyr Ala Leu Ile Lys Gly Il - #e Ile Leu Arg Lys Ile# 335- Phe Thr Thr Ile Ser Phe Cys Ile Val Leu Ar - #g Met Ala Val Thr Arg# 350- Gln Phe Pro Trp Ala Val Gln Thr Trp Tyr As - #p Ser Leu Gly Ala Ile# 365- Asn Lys Ile Gln Asp Phe Leu Gln Lys Gln Gl - #u Tyr Lys Thr Leu Glu# 380- Tyr Asn Leu Thr Thr Thr Glu Val Val Met Gl - #u Asn Val Thr Ala Phe385 3 - #90 3 - #95 4 -#00- Trp Glu Glu Gly Phe Gly Glu Leu Phe Glu Ly - #s Ala Lys Gln Asn Asn# 415- Asn Asn Arg Lys Thr Ser Asn Gly Asp Asp Se - #r Leu Phe Phe Ser Asn# 430- Phe Ser Leu Leu Gly Thr Pro Val Leu Lys As - #p Ile Asn Phe Lys Ile# 445- Glu Arg Gly Gln Leu Leu Ala Val Ala Gly Se - #r Thr Gly Ala Gly Lys# 460- Thr Ser Leu Leu Met Met Ile Met Gly Glu Le - #u Glu Pro Ser Glu Gly465 4 - #70 4 - #75 4 -#80- Lys Ile Lys His Ser Gly Arg Ile Ser Phe Cy - #s Ser Gln Phe Ser Trp# 495- Ile Met Pro Gly Thr Ile Lys Glu Asn Ile Il - #e Gly Val Ser Tyr Asp# 510- Glu Tyr Arg Tyr Arg Ser Val Ile Lys Ala Cy - #s Gln Leu Glu Glu Asp# 525- Ile Ser Lys Phe Ala Glu Lys Asp Asn Ile Va - #l Leu Gly Glu Gly Gly# 540- Ile Thr Leu Ser Gly Gly Gln Arg Ala Arg Il - #e Ser Leu Ala Arg Ala545 5 - #50 5 - #55 5 -#60- Val Tyr Lys Asp Ala Asp Leu Tyr Leu Leu As - #p Ser Pro Phe Gly Tyr# 575- Leu Asp Val Leu Thr Glu Lys Glu Ile Phe Gl - #u Ser Cys Val Cys Lys# 590- Leu Met Ala Asn Lys Thr Arg Ile Leu Val Th - #r Ser Lys Met Glu His# 605- Leu Lys Lys Ala Asp Lys Ile Leu Ile Leu As - #n Glu Gly Ser Ser Tyr# 620- Phe Tyr Gly Thr Phe Ser Glu Leu Gln Asn Le - #u Gln Pro Asp Phe Ser625 6 - #30 6 - #35 6 -#40- Ser Lys Leu Met Gly Cys Asp Ser Phe Asp Gl - #n Phe Ser Ala Glu Arg# 655- Arg Asn Ser Ile Leu Thr Glu Thr Leu His Ar - #g Phe Ser Leu Glu Gly# 670- Asp Ala Pro Val Ser Trp Thr Glu Thr Lys Ly - #s Gln Ser Phe Lys Gln# 685- Thr Gly Glu Phe Gly Glu Lys Arg Lys Asn Se - #r Ile Leu Asn Pro Ile# 700- Asn Ser Ile Arg Lys Phe Ser Ile Val Gln Ly - #s Thr Pro Leu Gln Met705 7 - #10 7 - #15 7 -#20- Asn Gly Ile Glu Glu Asp Ser Asp Glu Pro Le - #u Glu Arg Arg Leu Ser# 735- Leu Val Pro Asp Ser Glu Gln Gly Glu Ala Il - #e Leu Pro Arg Ile Ser# 750- Val Ile Ser Thr Gly Pro Thr Leu Gln Ala Ar - #g Arg Arg Gln Ser Val# 765- Leu Asn Leu Met Thr His Ser Val Asn Gln Gl - #y Gln Asn Ile His Arg# 780- Lys Thr Thr Ala Ser Thr Arg Lys Val Ser Le - #u Ala Pro Gln Ala Asn785 7 - #90 7 - #95 8 -#00- Leu Thr Glu Leu Asp Ile Tyr Ser Arg Arg Le - #u Ser Gln Glu Thr Gly# 815- Leu Glu Ile Ser Glu Glu Ile Asn Glu Glu As - #p Leu Lys Glu Cys Leu# 830- Phe Asp Asp Met Glu Ser Ile Pro Ala Val Th - #r Thr Trp Asn Thr Tyr# 845- Leu Arg Tyr Ile Thr Val His Lys Ser Leu Il - #e Phe Val Leu Ile Trp# 860- Cys Leu Val Ile Phe Leu Ala Glu Val Ala Al - #a Ser Leu Val Val Leu865 8 - #70 8 - #75 8 -#80- Trp Leu Leu Gly Asn Thr Pro Leu Gln Asp Ly - #s Gly Asn Ser Thr His# 895- Ser Arg Asn Asn Ser Tyr Ala Val Ile Ile Th - #r Ser Thr Ser Ser Tyr# 910- Tyr Val Phe Tyr Ile Tyr Val Gly Val Ala As - #p Thr Leu Leu Ala Met# 925- Gly Phe Phe Arg Gly Leu Pro Leu Val His Th - #r Leu Ile Thr Val Ser# 940- Lys Ile Leu His His Lys Met Leu His Ser Va - #l Leu Gln Ala Pro Met945 9 - #50 9 - #55 9 -#60- Ser Thr Leu Asn Thr Leu Lys Ala Gly Gly Il - #e Leu Asn Arg Phe Ser# 975- Lys Asp Ile Ala Ile Leu Asp Asp Leu Leu Pr - #o Leu Thr Ile Phe Asp# 990- Phe Ile Gln Leu Leu Leu Ile Val Ile Gly Al - #a Ile Ala Val Val Ala# 10050- Val Leu Gln Pro Tyr Ile Phe Val Ala Thr Va - #l Pro Val Ile Val Ala# 10205- Phe Ile Met Leu Arg Ala Tyr Phe Leu Gln Th - #r Ser Gln Gln Leu Lys# 10401030 - # 1035- Gln Leu Glu Ser Glu Gly Arg Ser Pro Ile Ph - #e Thr His Leu Val Thr# 10550- Ser Leu Lys Gly Leu Trp Thr Leu Arg Ala Ph - #e Gly Arg Gln Pro Tyr# 10705- Phe Glu Thr Leu Phe His Lys Ala Leu Asn Le - #u His Thr Ala Asn Trp# 10850- Phe Leu Tyr Leu Ser Thr Leu Arg Trp Phe Gl - #n Met Arg Ile Glu Met# 11005- Ile Phe Val Ile Phe Phe Ile Ala Val Thr Ph - #e Ile Ser Ile Leu Thr# 11201110 - # 1115- Thr Gly Glu Gly Glu Gly Arg Val Gly Ile Il - #e Leu Thr Leu Ala Met# 11350- Asn Ile Met Ser Thr Leu Gln Trp Ala Val As - #n Ser Ser Ile Asp Val# 11505- Asp Ser Leu Met Arg Ser Val Ser Arg Val Ph - #e Lys Phe Ile Asp Met# 11650- Pro Thr Glu Gly Lys Pro Thr Lys Ser Thr Ly - #s Pro Tyr Lys Asn Gly# 11805- Gln Leu Ser Lys Val Met Ile Ile Glu Asn Se - #r His Val Lys Lys Asp# 12001190 - # 1195- Asp Ile Trp Pro Ser Gly Gly Gln Met Thr Va - #l Lys Asp Leu Thr Ala# 12150- Lys Tyr Thr Glu Gly Gly Asn Ala Ile Leu Gl - #u Asn Ile Ser Phe Ser# 12305- Ile Ser Pro Gly Gln Arg Val Gly Leu Leu Gl - #y Arg Thr Gly Ser Gly# 12450- Lys Ser Thr Leu Leu Ser Ala Phe Leu Arg Le - #u Leu Asn Thr Glu Gly# 12605- Glu Ile Gln Ile Asp Gly Val Ser Trp Asp Se - #r Ile Thr Leu Gln Gln# 12801270 - # 1275- Trp Arg Lys Ala Phe Gly Val Ile Pro Gln Ly - #s Val Phe Ile Phe Ser# 12950- Gly Thr Phe Arg Lys Asn Leu Asp Pro Tyr Gl - #u Gln Trp Ser Asp Gln# 13105- Glu Ile Trp Lys Val Ala Asp Glu Val Gly Le - #u Arg Ser Val Ile Glu# 13250- Gln Phe Pro Gly Lys Leu Asp Phe Val Leu Va - #l Asp Gly Gly Cys Val# 13405- Leu Ser His Gly His Lys Gln Leu Met Cys Le - #u Ala Arg Ser Val Leu# 13601350 - # 1355- Ser Lys Ala Lys Ile Leu Leu Leu Asp Glu Pr - #o Ser Ala His Leu Asp# 13750- Pro Val Thr Tyr Gln Ile Ile Arg Arg Thr Le - #u Lys Gln Ala Phe Ala# 13905- Asp Cys Thr Val Ile Leu Cys Glu His Arg Il - #e Glu Ala Met Leu Glu# 14050- Cys Gln Gln Phe Leu Val Ile Glu Glu Asn Ly - #s Val Arg Gln Tyr Asp# 14205- Ser Ile Gln Lys Leu Leu Asn Glu Arg Ser Le - #u Phe Arg Gln Ala Ile# 14401430 - # 1435- Ser Pro Ser Asp Arg Val Lys Leu Phe Pro Hi - #s Arg Asn Ser Ser Lys# 14550- Cys Lys Ser Lys Pro Gln Ile Ala Ala Leu Ly - #s Glu Glu Thr Glu Glu# 14705- Glu Val Gln Asp Thr Arg Leu 1475- (2) INFORMATION FOR SEQ ID NO:5:- (i) SEQUENCE CHARACTERISTICS:#pairs (A) LENGTH: 6129 base (B) TYPE: nucleic acid (C) STRANDEDNESS: single (D) TOPOLOGY: linear- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:- AATTGGAAGC AAATGACATC ACAGCAGGTC AGAGAAAAAG GGTTGAGCGG CA - #GGCACCCA 60- GAGTAGTAGG TCTTTGGCAT TAGGAGCTTG AGCCCAGACG GCCCTAGCAG GG - #ACCCCAGC 120- GCCCGAGAGA CCATGCAGAG GTCGCCTCTG GAAAAGGCCA GCGTTGTCTC CA - #AACTTTTT 180- TTCAGCTGGA CCAGACCAAT TTTGAGGAAA GGATACAGAC AGCGCCTGGA AT - #TGTCAGAC 240- ATATACCAAA TCCCTTCTGT TGATTCTGCT GACAATCTAT CTGAAAAATT GG - #AAAGAGAA 300- TGGGATAGAG AGCTGGCTTC AAAGAAAAAT CCTAAACTCA TTAATGCCCT TC - #GGCGATGT 360- TTTTTCTGGA GATTTATGTT CTATGGAATC TTTTTATATT TAGGGGAAGT CA - #CCAAAGCA 420- GTACAGCCTC TCTTACTGGG AAGAATCATA GCTTCCTATG ACCCGGATAA CA - #AGGAGGAA 480- CGCTCTATCG CGATTTATCT AGGCATAGGC TTATGCCTTC TCTTTATTGT GA - #GGACACTG 540- CTCCTACACC CAGCCATTTT TGGCCTTCAT CACATTGGAA TGCAGATGAG AA - #TAGCTATG 600- TTTAGTTTGA TTTATAAGAA GACTTTAAAG CTGTCAAGCC GTGTTCTAGA TA - #AAATAAGT 660- ATTGGACAAC TTGTTAGTCT CCTTTCCAAC AACCTGAACA AATTTGATGA AG - #GACTTGCA 720- TTGGCACATT TCGTGTGGAT CGCTCCTTTG CAAGTGGCAC TCCTCATGGG GC - #TAATCTGG 780- GAGTTGTTAC AGGCGTCTGC CTTCTGTGGA CTTGGTTTCC TGATAGTCCT TG - #CCCTTTTT 840- CAGGCTGGGC TAGGGAGAAT GATGATGAAG TACAGAGATC AGAGAGCTGG GA - #AGATCAGT 900- GAAAGACTTG TGATTACCTC AGAAATGATT GAAAATATCC AATCTGTTAA GG - #CATACTGC 960- TGGGAAGAAG CAATGGAAAA AATGATTGAA AACTTAAGAC AAACAGAACT GA - #AACTGACT1020- CGGAAGGCAG CCTATGTGAG ATACTTCAAT AGCTCAGCCT TCTTCTTCTC AG - #GGTTCTTT1080- GTGGTGTTTT TATCTGTGCT TCCCTATGCA CTAATCAAAG GAATCATCCT CC - #GGAAAATA1140- TTCACCACCA TCTCATTCTG CATTGTTCTG CGCATGGCGG TCACTCGGCA AT - #TTCCCTGG1200- GCTGTACAAA CATGGTATGA CTCTCTTGGA GCAATAAACA AAATACAGGA TT - #TCTTACAA1260- AAGCAAGAAT ATAAGACATT GGAATATAAC TTAACGACTA CAGAAGTAGT GA - #TGGAGAAT1320- GTAACAGCCT TCTGGGAGGA GGGATTTGGG GAATTATTTG AGAAAGCAAA AC - #AAAACAAT1380- AACAATAGAA AAACTTCTAA TGGTGATGAC AGCCTCTTCT TCAGTAATTT CT - #CACTTCTT1440- GGTACTCCTG TCCTGAAAGA TATTAATTTC AAGATAGAAA GAGGACAGTT GT - #TGGCGGTT1500- GCTGGATCCA CTGGAGCAGG CAAGACTTCA CTTCTAATGA TGATTATGGG AG - #AACTGGAG1560- CCTTCAGAGG GTAAAATTAA GCACAGTGGA AGAATTTCAT TCTGTTCTCA GT - #TTTCCTGG1620- ATTATGCCTG GCACCATTAA AGAAAATATC ATCTTTGGTG TTTCCTATGA TG - #AATATAGA1680- TACAGAAGCG TCATCAAAGC ATGCCAACTA GAAGAGGACA TCTCCAAGTT TG - #CAGAGAAA1740- GACAATATAG TTCTTGGAGA AGGTGGAATC ACACTGAGTG GAGAYCAACG AG - #CAAGAATT1800- TCTTTAGCAA GAGCAGTATA CAAAGATGCT GATTTGTATT TATTAGACTC TC - #CTTTTGGA1860- TACCTAGATG TTTTAACAGA AAAAGAAATA TTTGAAAGCT GTGTCTGTAA AC - #TGATGGCT1920- AACAAAACTA GGATTTTGGT CACTTCTAAA ATGGAACATT TAAAGAAAGC TG - #ACAAAATA1980- TTAATTTTGA ATGAAGGTAG CAGCTATTTT TATGGGACAT TTTCAGAACT CC - #AAAATCTA2040- CAGCCAGACT TTAGCTCAAA ACTCATGGGA TGTGATTCTT TCGACCAATT TA - #GTGCAGAA2100- AGAAGAAATT CAATCCTAAC TGAGACCTTA CACCGTTTCT CATTAGAAGG AG - #ATGCTCCT2160- GTCTCCTGGA CAGAAACAAA AAAACAATCT TTTAAACAGA CTGGAGAGTT TG - #GGGAAAAA2220- AGGAAGAATT CTATTCTCAA TCCAATCAAC TCTATACGAA AATTTTCCAT TG - #TGCAAAAG2280- ACTCCCTTAC AAATGAATGG CATCGAAGAG GATTCTGATG AGCCTTTAGA GA - #GAAGGCTG2340- TCCTTAGTAC CAGATTCTGA GCAGGGAGAG GCGATACTGC CTCGCATCAG CG - #TGATCAGC2400- ACTGGCCCCA CGCTTCAGGC ACGAAGGAGG CAGTCTGTCC TGAACCTGAT GA - #CACACTCA2460- GTTAACCAAG GTCAGAACAT TCACCGAAAG ACAACAGCAT CCACACGAAA AG - #TGTCACTG2520- GCCCCTCAGG CAAACTTGAC TGAACTGGAT ATATATTCAA GAAGGTTATC TC - #AAGAAACT2580- GGCTTGGAAA TAAGTGAAGA AATTAACGAA GAAGACTTAA AGGAGTGCCT TT - #TTGATGAT2640- ATGGAGAGCA TACCAGCAGT GACTACATGG AACACATACC TTCGATATAT TA - #CTGTCCAC2700- AAGAGCTTAA TTTTTGTGCT AATTTGGTGC TTAGTAATTT TTCTGGCAGA GG - #TGGCTGCT2760- TCTTTGGTTG TGCTGTGGCT CCTTGGAAAC ACTCCTCTTC AAGACAAAGG GA - #ATAGTACT2820- CATAGTAGAA ATAACAGCTA TGCAGTGATT ATCACCAGCA CCAGTTCGTA TT - #ATGTGTTT2880- TACATTTACG TGGGAGTAGC CGACACTTTG CTTGCTATGG GATTCTTCAG AG - #GTCTACCA2940- CTGGTGCATA CTCTAATCAC AGTGTCGAAA ATTTTACACC ACAAAATGTT AC - #ATTCTGTT3000- CTTCAAGCAC CTATGTCAAC CCTCAACACG TTGAAAGCAG GTGGGATTCT TA - #ATAGATTC3060- TCCAAAGATA TAGCAATTTT GGATGACCTT CTGCCTCTTA CCATATTTGA CT - #TCATCCAG3120- TTGTTATTAA TTGTGATTGG AGCTATAGCA GTTGTCGCAG TTTTACAACC CT - #ACATCTTT3180- GTTGCAACAG TGCCAGTGAT AGTGGCTTTT ATTATGTTGA GAGCATATTT CC - #TCCAAACC3240- TCACAGCAAC TCAAACAACT GGAATCTGAA GGCAGGAGTC CAATTTTCAC TC - #ATCTTGTT3300- ACAAGCTTAA AAGGACTATG GACACTTCGT GCCTTCGGAC GGCAGCCTTA CT - #TTGAAACT3360- CTGTTCCACA AAGCTCTGAA TTTACATACT GCCAACTGGT TCTTGTACCT GT - #CAACACTG3420- CGCTGGTTCC AAATGAGAAT AGAAATGATT TTTGTCATCT TCTTCATTGC TG - #TTACCTTC3480- ATTTCCATTT TAACAACAGG AGAAGGAGAA GGAAGAGTTG GTATTATCCT GA - #CTTTAGCC3540- ATGAATATCA TGAGTACATT GCAGTGGGCT GTAAACTCCA GCATAGATGT GG - #ATAGCTTG3600- ATGCGATCTG TGAGCCGAGT CTTTAAGTTC ATTGACATGC CAACAGAAGG TA - #AACCTACC3660- AAGTCAACCA AACCATACAA GAATGGCCAA CTCTCGAAAG TTATGATTAT TG - #AGAATTCA3720- CACGTGAAGA AAGATGACAT CTGGCCCTCA GGGGGCCAAA TGACTGTCAA AG - #ATCTCACA3780- GCAAAATACA CAGAAGGTGG AAATGCCATA TTAGAGAACA TTTCCTTCTC AA - #TAAGTCCT3840- GGCCAGAGGG TGGGCCTCTT GGGAAGAACT GGATCAGGGA AGAGTACTTT GT - #TATCAGCT3900- TTTTTGAGAC TACTGAACAC TGAAGGAGAA ATCCAGATCG ATGGTGTGTC TT - #GGGATTCA3960- ATAACTTTGC AACAGTGGAG GAAAGCCTTT GGAGTGATAC CACAGAAAGT AT - #TTATTTTT4020- TCTGGAACAT TTAGAAAAAA CTTGGATCCC TATGAACAGT GGAGTGATCA AG - #AAATATGG4080- AAAGTTGCAG ATGAGGTTGG GCTCAGATCT GTGATAGAAC AGTTTCCTGG GA - #AGCTTGAC4140- TTTGTCCTTG TGGATGGGGG CTGTGTCCTA AGCCATGGCC ACAAGCAGTT GA - #TGTGCTTG4200- GCTAGATCTG TTCTCAGTAA GGCGAAGATC TTGCTGCTTG ATGAACCCAG TG - #CTCATTTG4260- GATCCAGTAA CATACCAAAT AATTAGAAGA ACTCTAAAAC AAGCATTTGC TG - #ATTGCACA4320- GTAATTCTCT GTGAACACAG GATAGAAGCA ATGCTGGAAT GCCAACAATT TT - #TGGTCATA4380- GAAGAGAACA AAGTGCGGCA GTACGATTCC ATCCAGAAAC TGCTGAACGA GA - #GGAGCCTC4440- TTCCGGCAAG CCATCAGCCC CTCCGACAGG GTGAAGCTCT TTCCCCACCG GA - #ACTCAAGC4500- AAGTGCAAGT CTAAGCCCCA GATTGCTGCT CTGAAAGAGG AGACAGAAGA AG - #AGGTGCAA4560- GATACAAGGC TTTAGAGAGC AGCATAAATG TTGACATGGG ACATTTGCTC AT - #GGAATTGG4620- AGCTCGTGGG ACAGTCACCT CATGGAATTG GAGCTCGTGG AACAGTTACC TC - #TGCCTCAG4680- AAAACAAGGA TGAATTAAGT TTTTTTTTAA AAAAGAAACA TTTGGTAAGG GG - #AATTGAGG4740- ACACTGATAT GGGTCTTGAT AAATGGCTTC CTGGCAATAG TCAAATTGTG TG - #AAAGGTAC4800- TTCAAATCCT TGAAGATTTA CCACTTGTGT TTTGCAAGCC AGATTTTCCT GA - #AAACCCTT4860- GCCATGTGCT AGTAATTGGA AAGGCAGCTC TAAATGTCAA TCAGCCTAGT TG - #ATCAGCTT4920- ATTGTCTAGT GAAACTCGTT AATTTGTAGT GTTGGAGAAG AACTGAAATC AT - #ACTTCTTA4980- GGGTTATGAT TAAGTAATGA TAACTGGAAA CTTCAGCGGT TTATATAAGC TT - #GTATTCCT5040- TTTTCTCTCC TCTCCCCATG ATGTTTAGAA ACACAACTAT ATTGTTTGCT AA - #GCATTCCA5100- ACTATCTCAT TTCCAAGCAA GTATTAGAAT ACCACAGGAA CCACAAGACT GC - #ACATCAAA5160- ATATGCCCCA TTCAACATCT AGTGAGCAGT CAGGAAAGAG AACTTCCAGA TC - #CTGGAAAT5220- CAGGGTTAGT ATTGTCCAGG TCTACCAAAA ATCTCAATAT TTCAGATAAT CA - #CAATACAT5280- CCCTTACCTG GGAAAGGGCT GTTATAATCT TTCACAGGGG ACAGGATGGT TC - #CCTTGATG5340- AAGAAGTTGA TATGCCTTTT CCCAACTCCA GAAAGTGACA AGCTCACAGA CC - #TTTGAACT5400- AGAGTTTAGC TGGAAAAGTA TGTTAGTGCA AATTGTCACA GGACAGCCCT TC - #TTTCCACA5460- GAAGCTCCAG GTAGAGGGTG TGTAAGTAGA TAGGCCATGG GCACTGTGGG TA - #GACACACA5520- TGAAGTCCAA GCATTTAGAT GTATAGGTTG ATGGTGGTAT GTTTTCAGGC TA - #GATGTATG5580- TACTTCATGC TGTCTACACT AAGAGAGAAT GAGAGACACA CTGAAGAAGC AC - #CAATCATG5640- AATTAGTTTT ATATGCTTCT GTTTTATAAT TTTGTGAAGC AAAATTTTTT CT - #CTAGGAAA5700- TATTTATTTT AATAATGTTT CAAACATATA TTACAATGCT GTATTTTAAA AG - #AATGATTA5760- TGAATTACAT TTGTATAAAA TAATTTTTAT ATTTGAAATA TTGACTTTTT AT - #GGCACTAG5820- TATTTTTATG AAATATTATG TTAAAACTGG GACAGGGGAG AACCTAGGGT GA - #TATTAACC5880- AGGGGCCATG AATCACCTTT TGGTCTGGAG GGAAGCCTTG GGGCTGATCG AG - #TTGTTGCC5940- CACAGCTGTA TGATTCCCAG CCAGACACAG CCTCTTAGAT GCAGTTCTGA AG - #AAGATGGT6000- ACCACCAGTC TGACTGTTTC CATCAAGGGT ACACTGCCTT CTCAACTCCA AA - #CTGACTCT6060- TAAGAAGACT GCATTATATT TATTACTGTA AGAAAATATC ACTTGTCAAT AA - #AATCCATA6120# 6129- (2) INFORMATION FOR SEQ ID NO:6:- (i) SEQUENCE CHARACTERISTICS:#acids (A) LENGTH: 1480 amino (B) TYPE: amino acid (C) STRANDEDNESS: (D) TOPOLOGY: linear- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:- Met Gln Arg Ser Pro Leu Glu Lys Ala Ser Va - #l Val Ser Lys Leu Phe# 15- Phe Ser Trp Thr Arg Pro Ile Leu Arg Lys Gl - #y Tyr Arg Gln Arg Leu# 30- Glu Leu Ser Asp Ile Tyr Gln Ile Pro Ser Va - #l Asp Ser Ala Asp Asn# 45- Leu Ser Glu Lys Leu Glu Arg Glu Trp Asp Ar - #g Glu Leu Ala Ser Lys# 60- Lys Asn Pro Lys Leu Ile Asn Ala Leu Arg Ar - #g Cys Phe Phe Trp Arg#80- Phe Met Phe Tyr Gly Ile Phe Leu Tyr Leu Gl - #y Glu Val Thr Lys Ala# 95- Val Gln Pro Leu Leu Leu Gly Arg Ile Ile Al - #a Ser Tyr Asp Pro Asp# 110- Asn Lys Glu Glu Arg Ser Ile Ala Ile Tyr Le - #u Gly Ile Gly Leu Cys# 125- Leu Leu Phe Ile Val Arg Thr Leu Leu Leu Hi - #s Pro Ala Ile Phe Gly# 140- Leu His His Ile Gly Met Gln Met Arg Ile Al - #a Met Phe Ser Leu Ile145 1 - #50 1 - #55 1 -#60- Tyr Lys Lys Thr Leu Lys Leu Ser Ser Arg Va - #l Leu Asp Lys Ile Ser# 175- Ile Gly Gln Leu Val Ser Leu Leu Ser Asn As - #n Leu Asn Lys Phe Asp# 190- Glu Gly Leu Ala Leu Ala His Phe Val Trp Il - #e Ala Pro Leu Gln Val# 205- Ala Leu Leu Met Gly Leu Ile Trp Glu Leu Le - #u Gln Ala Ser Ala Phe# 220- Cys Gly Leu Gly Phe Leu Ile Val Leu Ala Le - #u Phe Gln Ala Gly Leu225 2 - #30 2 - #35 2 -#40- Gly Arg Met Met Met Lys Tyr Arg Asp Gln Ar - #g Ala Gly Lys Ile Ser# 255- Glu Arg Leu Val Ile Thr Ser Glu Met Ile Gl - #u Asn Ile Gln Ser Val# 270- Lys Ala Tyr Cys Trp Glu Glu Ala Met Glu Ly - #s Met Ile Glu Asn Leu# 285- Arg Gln Thr Glu Leu Lys Leu Thr Arg Lys Al - #a Ala Tyr Val Arg Tyr# 300- Phe Asn Ser Ser Ala Phe Phe Phe Ser Gly Ph - #e Phe Val Val Phe Leu305 3 - #10 3 - #15 3 -#20- Ser Val Leu Pro Tyr Ala Leu Ile Lys Gly Il - #e Ile Leu Arg Lys Ile# 335- Phe Thr Thr Ile Ser Phe Cys Ile Val Leu Ar - #g Met Ala Val Thr Arg# 350- Gln Phe Pro Trp Ala Val Gln Thr Trp Tyr As - #p Ser Leu Gly Ala Ile# 365- Asn Lys Ile Gln Asp Phe Leu Gln Lys Gln Gl - #u Tyr Lys Thr Leu Glu# 380- Tyr Asn Leu Thr Thr Thr Glu Val Val Met Gl - #u Asn Val Thr Ala Phe385 3 - #90 3 - #95 4 -#00- Trp Glu Glu Gly Phe Gly Glu Leu Phe Glu Ly - #s Ala Lys Gln Asn Asn# 415- Asn Asn Arg Lys Thr Ser Asn Gly Asp Asp Se - #r Leu Phe Phe Ser Asn# 430- Phe Ser Leu Leu Gly Thr Pro Val Leu Lys As - #p Ile Asn Phe Lys Ile# 445- Glu Arg Gly Gln Leu Leu Ala Val Ala Gly Se - #r Thr Gly Ala Gly Lys# 460- Thr Ser Leu Leu Met Met Ile Met Gly Glu Le - #u Glu Pro Ser Glu Gly465 4 - #70 4 - #75 4 -#80- Lys Ile Lys His Ser Gly Arg Ile Ser Phe Cy - #s Ser Gln Phe Ser Trp# 495- Ile Met Pro Gly Thr Ile Lys Glu Asn Ile Il - #e Phe Gly Val Ser Tyr# 510- Asp Glu Tyr Arg Tyr Arg Ser Val Ile Lys Al - #a Cys Gln Leu Glu Glu# 525- Asp Ile Ser Lys Phe Ala Glu Lys Asp Asn Il - #e Val Leu Gly Glu Gly# 540- Gly Ile Thr Leu Ser Gly Asp Gln Arg Ala Ar - #g Ile Ser Leu Ala Arg545 5 - #50 5 - #55 5 -#60- Ala Val Tyr Lys Asp Ala Asp Leu Tyr Leu Le - #u Asp Ser Pro Phe Gly# 575- Tyr Leu Asp Val Leu Thr Glu Lys Glu Ile Ph - #e Glu Ser Cys Val Cys# 590- Lys Leu Met Ala Asn Lys Thr Arg Ile Leu Va - #l Thr Ser Lys Met Glu# 605- His Leu Lys Lys Ala Asp Lys Ile Leu Ile Le - #u Asn Glu Gly Ser Ser# 620- Tyr Phe Tyr Gly Thr Phe Ser Glu Leu Gln As - #n Leu Gln Pro Asp Phe625 6 - #30 6 - #35 6 -#40- Ser Ser Lys Leu Met Gly Cys Asp Ser Phe As - #p Gln Phe Ser Ala Glu# 655- Arg Arg Asn Ser Ile Leu Thr Glu Thr Leu Hi - #s Arg Phe Ser Leu Glu# 670- Gly Asp Ala Pro Val Ser Trp Thr Glu Thr Ly - #s Lys Gln Ser Phe Lys# 685- Gln Thr Gly Glu Phe Gly Glu Lys Arg Lys As - #n Ser Ile Leu Asn Pro# 700- Ile Asn Ser Ile Arg Lys Phe Ser Ile Val Gl - #n Lys Thr Pro Leu Gln705 7 - #10 7 - #15 7 -#20- Met Asn Gly Ile Glu Glu Asp Ser Asp Glu Pr - #o Leu Glu Arg Arg Leu# 735- Ser Leu Val Pro Asp Ser Glu Gln Gly Glu Al - #a Ile Leu Pro Arg Ile# 750- Ser Val Ile Ser Thr Gly Pro Thr Leu Gln Al - #a Arg Arg Arg Gln Ser# 765- Val Leu Asn Leu Met Thr His Ser Val Asn Gl - #n Gly Gln Asn Ile His# 780- Arg Lys Thr Thr Ala Ser Thr Arg Lys Val Se - #r Leu Ala Pro Gln Ala785 7 - #90 7 - #95 8 -#00- Asn Leu Thr Glu Leu Asp Ile Tyr Ser Arg Ar - #g Leu Ser Gln Glu Thr# 815- Gly Leu Glu Ile Ser Glu Glu Ile Asn Glu Gl - #u Asp Leu Lys Glu Cys# 830- Leu Phe Asp Asp Met Glu Ser Ile Pro Ala Va - #l Thr Thr Trp Asn Thr# 845- Tyr Leu Arg Tyr Ile Thr Val His Lys Ser Le - #u Ile Phe Val Leu Ile# 860- Trp Cys Leu Val Ile Phe Leu Ala Glu Val Al - #a Ala Ser Leu Val Val865 8 - #70 8 - #75 8 -#80- Leu Trp Leu Leu Gly Asn Thr Pro Leu Gln As - #p Lys Gly Asn Ser Thr# 895- His Ser Arg Asn Asn Ser Tyr Ala Val Ile Il - #e Thr Ser Thr Ser Ser# 910- Tyr Tyr Val Phe Tyr Ile Tyr Val Gly Val Al - #a Asp Thr Leu Leu Ala# 925- Met Gly Phe Phe Arg Gly Leu Pro Leu Val Hi - #s Thr Leu Ile Thr Val# 940- Ser Lys Ile Leu His His Lys Met Leu His Se - #r Val Leu Gln Ala Pro945 9 - #50 9 - #55 9 -#60- Met Ser Thr Leu Asn Thr Leu Lys Ala Gly Gl - #y Ile Leu Asn Arg Phe# 975- Ser Lys Asp Ile Ala Ile Leu Asp Asp Leu Le - #u Pro Leu Thr Ile Phe# 990- Asp Phe Ile Gln Leu Leu Leu Ile Val Ile Gl - #y Ala Ile Ala Val Val# 10050- Ala Val Leu Gln Pro Tyr Ile Phe Val Ala Th - #r Val Pro Val Ile Val# 10205- Ala Phe Ile Met Leu Arg Ala Tyr Phe Leu Gl - #n Thr Ser Gln Gln Leu# 10401030 - # 1035- Lys Gln Leu Glu Ser Glu Gly Arg Ser Pro Il - #e Phe Thr His Leu Val# 10550- Thr Ser Leu Lys Gly Leu Trp Thr Leu Arg Al - #a Phe Gly Arg Gln Pro# 10705- Tyr Phe Glu Thr Leu Phe His Lys Ala Leu As - #n Leu His Thr Ala Asn# 10850- Trp Phe Leu Tyr Leu Ser Thr Leu Arg Trp Ph - #e Gln Met Arg Ile Glu# 11005- Met Ile Phe Val Ile Phe Phe Ile Ala Val Th - #r Phe Ile Ser Ile Leu# 11201110 - # 1115- Thr Thr Gly Glu Gly Glu Gly Arg Val Gly Il - #e Ile Leu Thr Leu Ala# 11350- Met Asn Ile Met Ser Thr Leu Gln Trp Ala Va - #l Asn Ser Ser Ile Asp# 11505- Val Asp Ser Leu Met Arg Ser Val Ser Arg Va - #l Phe Lys Phe Ile Asp# 11650- Met Pro Thr Glu Gly Lys Pro Thr Lys Ser Th - #r Lys Pro Tyr Lys Asn# 11805- Gly Gln Leu Ser Lys Val Met Ile Ile Glu As - #n Ser His Val Lys Lys# 12001190 - # 1195- Asp Asp Ile Trp Pro Ser Gly Gly Gln Met Th - #r Val Lys Asp Leu Thr# 12150- Ala Lys Tyr Thr Glu Gly Gly Asn Ala Ile Le - #u Glu Asn Ile Ser Phe# 12305- Ser Ile Ser Pro Gly Gln Arg Val Gly Leu Le - #u Gly Arg Thr Gly Ser# 12450- Gly Lys Ser Thr Leu Leu Ser Ala Phe Leu Ar - #g Leu Leu Asn Thr Glu# 12605- Gly Glu Ile Gln Ile Asp Gly Val Ser Trp As - #p Ser Ile Thr Leu Gln# 12801270 - # 1275- Gln Trp Arg Lys Ala Phe Gly Val Ile Pro Gl - #n Lys Val Phe Ile Phe# 12950- Ser Gly Thr Phe Arg Lys Asn Leu Asp Pro Ty - #r Glu Gln Trp Ser Asp# 13105- Gln Glu Ile Trp Lys Val Ala Asp Glu Val Gl - #y Leu Arg Ser Val Ile# 13250- Glu Gln Phe Pro Gly Lys Leu Asp Phe Val Le - #u Val Asp Gly Gly Cys# 13405- Val Leu Ser His Gly His Lys Gln Leu Met Cy - #s Leu Ala Arg Ser Val# 13601350 - # 1355- Leu Ser Lys Ala Lys Ile Leu Leu Leu Asp Gl - #u Pro Ser Ala His Leu# 13750- Asp Pro Val Thr Tyr Gln Ile Ile Arg Arg Th - #r Leu Lys Gln Ala Phe# 13905- Ala Asp Cys Thr Val Ile Leu Cys Glu His Ar - #g Ile Glu Ala Met Leu# 14050- Glu Cys Gln Gln Phe Leu Val Ile Glu Glu As - #n Lys Val Arg Gln Tyr# 14205- Asp Ser Ile Gln Lys Leu Leu Asn Glu Arg Se - #r Leu Phe Arg Gln Ala# 14401430 - # 1435- Ile Ser Pro Ser Asp Arg Val Lys Leu Phe Pr - #o His Arg Asn Ser Ser# 14550- Lys Cys Lys Ser Lys Pro Gln Ile Ala Ala Le - #u Lys Glu Glu Thr Glu# 14705- Glu Glu Val Gln Asp Thr Arg Leu# 1480__________________________________________________________________________

Claims

1. A method for enhancing chloride transport in epithelial cells, comprising contacting epithelial cells with a compound selected from the group consisting of flavones and isoflavones, wherein the compound is capable of stimulating chloride transport, and wherein the compound is not genistein.

2. A method according to claim 1, wherein the compound is quercetin, apigenin, kaempferol or biochanin A.

3. A method according to claim 1, wherein the epithelial cells are airway epithelial cells.

4. A method according to claim 3, wherein the airway epithelial cells are present in a mammal.

5. A method according to claim 4, wherein the compound is administered orally.

6. A method according to claim 4, wherein the compound is administered by inhalation.

7. A method according to claim 1, wherein the epithelial cells are intestinal cells.

8. A method according to claim 7, wherein the intestinal epithelial cells are present in a mammal.

9. A method according to claim 7, wherein the compound is administered orally.

10. A method according to claim 1, wherein the compound is present within a pharmaceutical composition.

11. A method according to claim 1, wherein the epithelial cells produce a CFTR protein having a deletion at position 508.

12. A method for treating cystic fibrosis in a mammal, comprising administering to a mammal one or more compounds selected from the group consisting of flavones and isoflavones, wherein the compound is capable of stimulating chloride secretion, and wherein the compound is not genistein.

13. A method according to claim 12, wherein the compound is quercetin, apigenin, kaempferol or biochanin A.

14. A method according to claim 12, wherein the compound is administered orally.

15. A method according to claim 12, wherein the compound is administered by inhalation.

16. A method according to claim 12, wherein the compound is present within a pharmaceutical composition.

17. A method for increasing chloride ion conductance in airway epithelial cells of a patient afflicted with cystic fibrosis, wherein the patient's CFTR protein has a deletion at position 508, the method comprising administering to a mammal one or more compounds selected from the group consisting of flavones and isoflavones, wherein the compound is capable of stimulating chloride secretion.

18. A pharmaceutical composition for treatment of cystic fibrosis, comprising one or more flavones or isoflavones capable of stimulating chloride secretion in combination with a pharmaceutically acceptable carrier, where the composition does not comprise genistein as an active ingredient, and wherein the composition further comprises 4-phenylbutyrate.

19. A pharmaceutical composition for treatment of cystic fibrosis, comprising quercetin in combination with a pharmaceutically acceptable carriers and wherein the composition further comprises 4-phenylbutyrate.

20. A pharmaceutical composition for treatment of cystic fibrosis, comprising apigenin in combination with a pharmaceutically acceptable carrier, and wherein the composition further comprises 4-phenylbutyrate.

21. A pharmaceutical composition for treatment of cystic fibrosis, comprising kaempferol in combination with a pharmaceutically acceptable carriers and wherein the composition further comprises 4-phenylbutyrate.

22. A pharmaceutical composition for treatment of cystic fibrosis, comprising biochanin A in combination with a pharmaceutically acceptable carrier, and wherein the composition further comprises 4-phenylbutyrate.