TREA

Method, compositions, and apparatus for treating and preventing respiratory viral infections

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Information

  • Patent Grant
  • 5824706
  • Patent Number
    5,824,706
  • Date Filed
    Friday, March 3, 1995
    29 years ago
  • Date Issued
    Tuesday, October 20, 1998
    26 years ago
Information
Abstract
Respiratory viral infections may be effectively prevented or treated by administering an aerosol spray comprising a polyoxometalate to the lungs.
Description

BACKGROUND OF THE INVENTION
1. Field of the Invention
The present invention relates to a method of treating respiratory viral infections, compositions useful for treating and/or preventing respiratory viral infections, and apparatus for delivering such compositions. The present invention also relates to methods of treating herpes virus infection and hepadnavirus infection.
2. Discussion of the Background
Respiratory viral infections are an important cause of respiratory disease. Examples of such respiratory diseases arising from viral infection include influenza A, influenza B, and respiratory syncytial virus (RSV).
There are a number of drugs available for such respiratory viral infections, including ribavirin, amantadine, and rimantadine. However, none of these therapies are completely satisfactory. In particular, such drugs may be accompanied by side effects including nausea, hematological toxicity, and the development of resistant viruses.
Polyoxometalates are soluble inorganic cluster-like compounds formed principally of oxide anion and early transition metal cations. Some major polyoxometalate structural families are as follows: (1) the Keggin class (e.g., .alpha.-SiW.sub.12 O.sub.40.sup.4 -); (2) the Wells-Dawson class (e.g., P.sub.2 W.sub.18 O.sub.62.sup.6 -); (3) fragments from these structures (e.g., PW.sub.11 O.sub.39.sup.7 -); (4) the Keggin derived sandwich compounds (e.g., K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2, code name, HS058); (5) the hexametalates or the Lindquist class (e.g., W.sub.6 O.sub.19.sup.2 -), decatungstate (W.sub.10 O.sub.32.sup.4 -); and (6) the Preyssler ion �(NaP.sub.5 W.sub.30 O.sub.114).sup.14 - ! (Hill, C. L., et al, J. Med. Chem, vol. 33, pp. 2767-2772 (1990); Hill, C. L., et al, in Advances in Chemotheraoy of AIDS, Diasio, R. B., et al, Eds, Pergamon Press, New York, pp. 33-41 (1990)).
The potent and selective anti-human immunodeficiency virus type-1 (HIV-1) activity of polyoxometalates in infected human peripheral mononuclear (PBM) cells or cultured CD4+ T-cell lines has been reported by several workers. (Hill, C. L., et al, J. Med. Chem, vol. 33, pp. 2767-2772 (1990); Hill, C. L., et al, in Advances in Chemotherapy of AIDS, Diasio, R. B., et al, Eds, Pergamon Press, New York, pp. 33-41 (1990); Kim, G. S., et al, J. Med. Chem., vol. 37 (1994), Yamamoto, N. et al, Mol. Pharmacol., vol. 42, pp. 1109-1117 (1992)). Polyoxometalates have also been shown to be broadly inhibitory against retro-, myxo-, herpes-, toga-, rhabdo-and arena viruses replications in vitro (Ikeda S. et al, Antiviral Chem. Chemother., vol. 4, pp. 253-262 (1993); Yamamoto, N. et al, Mol. Pharmacol., vol. 42, pp. 1109-1117 (1992)). The mechanism of anti-HIV action may be attributed to inhibition of virus cell binding and inhibition of syncytium formation (Hill, C. L., et al, J. Med. Chem, vol. 33, pp. 2767-2772 (1990); Kim, G. S. et al, Unpublished work; Take, Y., et al, Antiviral Res., vol. 15, pp. 113-124 (1991)). A similar mechanism of antiviral action has also been suggested against influenza virus (FluV)-A and respiratory syncytial virus (RSV) (Ikeda S. et al, Antiviral Chem. Chemother., vol. 4, pp. 253-262 (1993)).
However, to date, there is no report of the treatment of respiratory viral infection by the administration of a polyoxometalate. Thus, there remains a need for a method of treating respiratory viral infections. There also remains a need for compositions and apparatus useful for treating respiratory viral infections. There also remains a need for treating human herpes virus infections and hepadnavirus infections.
SUMMARY OF THE INVENTION
Accordingly, it is one object of the present invention to provide novel methods for treating respiratory viral infections.
It is another object of the present invention to provide novel methods for preventing respiratory viral infections.
It is another object of the present invention to provide novel compositions for treating respiratory viral infections.
It is another object of the present invention to provide novel compositions for preventing respiratory viral infections.
It is another object of the present invention to provide apparatus for dispensing such compositions.
It is another object of the present invention to provide novel methods for treating human herpes virus infection.
These and other objects, which will become apparent during the following detailed description, have been achieved by the inventors' discovery that administration of an effective amount of polyoxometalate is effective for the treatment and prevention of respiratory viral infection and that polyoxometalates may be conveniently administered to the lungs of an animal in the form of an aerosol spray.
The inventors have also discovered that human herpes virus infection and human hepadnavirus infection may be effectively treated by administering an effective amount of a polyoxometalate.





BRIEF DESCRIPTION OF THE DRAWINGS
A more complete appreciation of the invention and many of the attendant advantages thereof will be readily obtained as the same becomes better understood by reference to the following detailed description when considered in connection with the accompanying drawings, wherein:
FIGS. 1a and b show the inhibitory effects of HS-058 on virus yield in MDCK cells infected with FluV-A. Cells were infected with a multiplicity of infection (moi) of 5.0 (FIG. 1a), or 0.005 (FIG. 1b). Cultures were treated with 4.4 EC.sub.50 (6.0 .mu.M) of HS-058 from 60 min before (.DELTA.) or 90 min after (.quadrature.) virus inoculation to the end of the experiment at 35.degree. C. Control (.circle-solid., mock treated) and experimental cultures were incubated at 37.degree. C. for 90 min after virus inoculation, washed 3 times with maintenance medium, and then incubated at 35.degree. C. with or without compound in medium; and
FIG. 2 shows the inhibitory effect of HS-058 against antigen synthesis and syncytium formation of RSV in HeLa cell monolayers. HeLa cells in Lab-Tec chamber were infected with 100 PFU/well of RSV and incubated at 37.degree. C. After virus adsorption to cells by incubation for 90 min, infected cultures were treated with 1.6, 6, and 25 .mu.M of HS-058 at 35.degree. C. At 48 hr after infection, cells were fixed with acetone and stained with anti-RSV rabbit serum conjugated with fluorescein isothiocyanate. Cells were observed under a fluorescent microscope, and the number of antigen positive cells per 10 microscopic fields (.circle-solid.) and number of infected cells in one syncytium (.smallcircle.) were counted.





DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS
Thus, in a first embodiment, the present invention provides a method for treating respiratory viral infections by administering an effective amount of a polyoxometalate. In the context of the present invention, the term polyoxometalate includes compounds of the formulae:
(BW.sub.12 O.sub.40).sup.5- (I)
(W.sub.10 O.sub.32).sup.4- (II)
(P.sub.2 W.sub.18 O.sub.62).sup.6- (III)
PW.sub.11 O.sub.39.sup.7- (IV)
SiW.sub.11 O.sub.39.sup.8- (V)
HSiW.sub.9 O.sub.34.sup.9- (VI)
HPW.sub.9 O.sub.34.sup.8- (VII)
(TM).sub.4 (PW.sub.9 O.sub.34).sub.2.sup.t- (VIII)
(TM).sub.4 (P.sub.2 W.sub.15 O.sub.56).sub.2.sup.t- (IX)
�NaP.sub.5 W.sub.30 O.sub.110 !.sup.14- (X)
(TM).sub.3 (PW.sub.9 O.sub.34).sub.2.sup.12- (XI)
P.sub.2 W.sub.18 O.sub.6.sup.6- (XII)
wherein TM is a divalent or trivalent transition metal ion, such as Mn.sup.+2, Fe.sup.+2, Fe.sup.+3, Co.sup.+2, Co.sup.+3, Ni.sup.+2, Cu.sup.+2 and Zn.sup.+2 and wherein t is the valence of the anion which varies with the valence of TM;
�A.sub.x W.sub.y Nb.sub.a O.sub.b !.sup.z- (XII)
in which A is one or more element selected from P, Si or Ge and x is zero or an integer from 1 to 40,
y is an integer from 1 to 10,
a is an integer from 1 to 8,
b is an integer from 15 to 150, and
z is an integer dependent upon the nature and oxidation state of element A,
and their aqua complexes and active fragments.
In the context of the anions of formula (XIV), preferred ions are those in which element A is selected from one or more of H, P, Ge and Si. Preferably, when x=0, y=6-a, a is an integer from 1 to 5 and b=19; when A=Si or Ge, x=2, y=18, a=6 and b=77, and when A=P, x=2 or 4, y=12, 15, 17 or 30, a=1, 3 or 6 and b=62 or 123. The skilled artisan will readily appreciate that a molecule/ionic structure does not exist for every value of each integer in the above formula; examples of active ingredients will be given hereafter.
Obviously, these anions will be administered in the form of a pharmaceutically acceptable salt containing one or more cations. The identity of the cation or cations is not particularly limited. Examples of suitable cations include H.sup.+, K.sup.+, Na.sup.+, NH.sub.4.sup.+, mono-, di-, tri, or tetra-(C.sub.1-4)-alkylammonium, mono, di, tri, or tetra-(C.sub.2-4)-alkanolammonium, monocationic naturally-occurring amino acids (such as histidinium, argininium, or lysinium), oligo- or polypeptides containing one or more protonated basic amino acid residues, or any other common mono- or dication.
Specific examples of the polyoxometalates which may be used in the present invention are given in Table 1.
TABLE 1__________________________________________________________________________CODE NUMBERS AND CHEMICAL FORMULAE OF POLYOXOMETALATES STRUCTURALCODE NUMBER FORMULAE FAMILY__________________________________________________________________________HS-003 �(NMP).sub.2 H!.sub.3 PW.sub.12 O.sub.40.sup.aHS-004 �(DMA).sub.2 H!.sub.3 PMo.sub.12 O.sub.40.sup.bHS-005 (HPA-23) (NH.sub.4).sub.17 Na�NaSb.sub.9 W.sub.21 O.sub.86 ! Inorganic CryptateHS-006 a- and b-H.sub.5 BW.sub.12 O.sub.40 (BT)HS-007 a- and b-H.sub.6 ZnW.sub.12 O.sub.40HS-009 a- and b-H.sub.6 P.sub.2 W.sub.18 O.sub.62HS-010 .alpha.-(NH.sub.4).sub.6 P.sub.2 W.sub.18 O.sub.62 Wells DawsonHS-011 K.sub.10 Cu.sub.4(H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H.s ub.2 OHS-012 K.sub.10 Co.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H. sub.2 OHS-013 Na.sub.7 PW.sub.11 O.sub.39HS-013A Na.sub.7 PW.sub.11 O.sub.39.20H.sub.2 O + 2 C.sub.6 H.sub.5 P(O)(OH).sub.2HS-014 (n-Bu.sub.4 N).sub.4 H.sub.3 PW.sub.11 O.sub.39HS-015 b-Na.sub.8 HPW.sub.9 O.sub.34HS-016 (n-Bu.sub.4 N).sub.3 PMoW.sub.11 O.sub.39HS-017 a-�(nBu).sub.4 N!.sub.4 Mo.sub.8 O.sub.26HS-018 (n-Bu.sub.4 N).sub.2 W.sub.6 O.sub.19HS-019 (n-Bu.sub.4 N).sub.2 Mo.sub.6 O.sub.19HS-020 a-(NH.sub.4).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40HS-021 a-(NH.sub.4).sub.n H.sub.(5-n) BW.sub.12 O.sub.40HS-022 a-K.sub.5 BW.sub.12 O.sub.40HS-023 K.sub.4 W.sub.4 O.sub.10 (O.sub.2)6HS-024 b-Na.sub.9 HSiW.sub.9 O.sub.34HS-025 Na.sub.6 H.sub.2 W.sub.12 O.sub.40HS-026 (NH.sub.4).sub.14 �NaP.sub.5 W.sub.30 O.sub.110 ! PreysslerHS-027 a-(NH.sub.4).sub.5 BW.sub.12 O.sub.40HS-028 a-Na.sub.5 BW.sub.12 O.sub.40HS-029 (NH.sub.4).sub.4 W.sub.10 O.sub.32HS-030 (Me.sub.4 N).sub.4 W.sub.10 O.sub.32HS-031 (HISH.sup.+).sub.n H.sub.(5-n)BW.sub.12 O.sub.40.sup.cHS-032 (LYSH.sup.+).sub.n H.sub.(5-n)BW.sub.12 O.sub.40.sup.dHS-033 (ARGH.sup.+).sub.n H.sub.(5-n)BW.sub.12 O.sub.40.sup.eHS-034 (HISH.sup.+).sub.n H.sub.(4-n)SiW.sub.12 O.sub.40HS-035 (LYSH.sup.+).sub.n H.sub.(4-n)SiW.sub.12 O.sub.40HS-036 (ARGH.sup.+).sub.n H.sub.(4-n)SiW.sub.12 O.sub.40HS-037 a-K.sub.8 SiW.sub.11 O.sub.39HS-037A a-K.sub.8 SiW.sub.11 O.sub.39HS-038 K.sub.10 (H.sub.2 W.sub.12 O.sub.42)HS-039 K.sub.12 Ni.sub.3 (II) (PW.sub.9 O.sub.34).sub.2.nH.sub.2 OHS-040 (NH.sub.4).sub.10 Co.sub.4 (II)(PW.sub.9 O.sub.34).sub.2..sub.n H.sub.2 OHS-041 K.sub.12 Pd.sub.3 (II)(PW.sub.9 O.sub.34).sub.2.nH.sub.2 OHS-042 Na.sub.12 P.sub.2 W.sub.15 O.sub.56.18H.sub.2 O Lacunary (Defect)HS-043 Na.sub.16 Cu.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).s ub.2.nH.sub.2 OHS-044 Na.sub.16 Zn.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).s ub.2.nH.sub.2 OHS-045 Na.sub.16 Co.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).s ub.2.nH.sub.2 OHS-052 Na.sub.16 Ni.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).s ub.2.nH.sub.2 O Wells-Dawson SandwichHS-053 Na.sub.16 Mn.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).n H.sub.2 O Wells-Dawson SandwichHS-054 Na.sub.16 Fe.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).s ub.2.nH.sub.2 O Wells-Dawson SandwichHS-055 K.sub.10 Zn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H. sub.2 O Keggin SandwichHS-056 K.sub.10 Ni.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.s ub.2 O Keggin SandwichHS-057 K.sub.10 Mn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.s ub.2 O Keggin SandwichHS-058 K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.s ub.2 O Keggin SandwichHS-059 K.sub.12 Cu.sub.3 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 OHS-060 K.sub.12 (Co H.sub.2 O).sub.3 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 OHS-061 K.sub.12 Zn.sub.3 (PW.sub.9 O.sub.34).sub.2.15H.sub.2 OHS-062 K.sub.12 Mn.sub.3 (PW.sub.9 O.sub.34).sub.2.15H.sub.2 OHS-063 K.sub.12 Fe.sub.3 (PW.sub.9 O.sub.34).sub.2.25H.sub.2 OHS-064 (ARGH.sup.+).sub.10 (NH.sub.4).sub.7 Na�NaSb.sub.9 W.sub.21 O.sub.86 !HS-065 (ARGH.sup.+).sub.5 HW.sub.11 O.sub.39.17H.sub.2 OHS-066 K.sub.7 Ti.sub.2 W.sub.10 O.sub.40HS-067 �(CH.sub.3).sub.4 N!.sub.7 Ti.sub.2 W.sub.10 O.sub.40HS-068 Cs.sub.7 Ti.sub.2 W.sub.10 O.sub.40HS-069 (HISH.sup.+ !.sub.7 Ti.sub.2 W.sub.10 O.sub.40HS-070 (LYSH.sup.+).sub.n Na.sub.7-n PTi.sub.2 W.sub.10 O.sub.40HS-071 (ARGH.sup.+).sub.n Na.sub.7-n PTi.sub.2 W.sub.10 O.sub.40HS-072 Cs.sub.4 �SiW.sub.11 O.sub.39.O(SiCH.sub.2 CH.sub.2 C(O)OCH.sub.3) .sub.2 !.sub.4 -HS-073 �TBA!.sub.3 H.sub.3 V.sub.10 O.sub.28.sup.fHS-074 K.sub.7 HNb.sub.6 O.sub.19.13H.sub.2 OHS-075 K.sub.8 Ta.sub.6 O.sub.19.17H.sub.2 OHS-076 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub .2 CH.sub.2 C(O)OCH.sub.3).sub.2HS-077 �CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 --(SiCH.sub.2 CH.sub.2 CH.sub.2 CN)HS-078 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 --(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl)HS-079 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 --(SiCH.dbd.C H.sub.2)HS-080 Cs.sub.4 �SiW.sub.11 O.sub.39 --(SiCH.sub.2 CH.sub.2 CH.sub.2 CN).sub.2 !HS-081 Cs.sub.4 �SiW.sub.11 O.sub.39 --(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl).sub.2 !HS-082 Cs.sub.4 �SiW.sub.11 O.sub.39 --(SiCH.dbd.CH.sub.2).sub.2 !HS-083 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 O(SiCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3).sub.2 Organic DerivatizedHS-084 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub .2 CH.sub.2 CH.sub.2 Cl).sub.2HS-085 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub .2 CH.sub.2 CH.sub.2 CN).sub.2HS-086 �(CH.sub.3).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 --O(SiCH.dbd.CH.sub .2).sub.2HS-087 �(CH.sub.2).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 --O(SiC(CH.sub.3).s ub.3).sub.2HS-088 �(CH.sub.3).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 --O(SiCH.sub.2 CH(CH.sub.3).sub.2).sub.2HS-089 �(CH.sub.3).sub.4 N.sup.+ !.sub.3 PW.sub.11 O.sub.39 O(SiCH.sub.2 CH.sub.2 COOCH.sub.3).sub.2 Organic DerivatizedHS-090 K.sub.5 Mn(II)PW.sub.11 O.sub.39 -nH.sub.2 OHS-091 K.sub.8 Mn(II)P.sub.2 W.sub.17 O.sub.61.nH.sub.2 O Transition Metal Substituted PolyoxometalateHS-092 K.sub.6 Mn(II)SiW.sub.11 O.sub.39 -nH.sub.2 OHS-093 K.sub.5 PW.sub.11 O.sub.39 (SiMe.sub.2).nH.sub.2 OHS-094 K.sub.3 PW.sub.11 O.sub.41 (PPh).sub.2.xH.sub.2 OHS-095 Na.sub.3 PW.sub.11 O.sub.41 (PPh).sub.2.xH.sub.2 OHS-096 K.sub.5 PTiW.sub.11 O.sub.40HS-097 Cs.sub.5 PTiW.sub.11 O.sub.39HS-098 K.sub.6 SiW.sub.11 O.sub.39 (SiMe.sub.2).nH.sub.2 OHS-099 K.sub.3 PW.sub.11 O.sub.41 (PEt).sub.2.nH.sub.2 OHS-100 KSiW.sub.11 O.sub.39 �SiPh(t-Bu)!.nH.sub.2 OHS-101 K.sub.6 SiW.sub.11 O.sub.39 (SiPh.sub.2).nH.sub.2 OHS-102 K.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 OHS-103 Cs.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 OHS-104 Cs.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 OHS-105 (Me.sub.3 NH).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O Substituted KegginHS-107 (CN.sub.3 H.sub.6).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 OHS-108 (CN.sub.3 H.sub.6).sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.su b.2 OHS-109 Rb.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 OHS-110 Rb.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 OHS-111 K.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 OHS-112 K.sub.6 P.sub.2 Mo.sub.18 O.sub.62.nH.sub.2 OHS-113 (C.sub.5 H.sub.5 N).sub.7 HSi.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH. sub.2 OHS-114 (C.sub.5 H.sub.5 N).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 OHS-115 (ARGH.sup.+).sub.8 SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 OHS-116 (LYSH.sup.+).sub.7 K SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 OHS-117 (HISH.sup.+).sub.6 K.sub.2 SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 OHS-118a H.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O(2 batches)HS-119 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub .2 CH.sub.3).sub.2HS-120 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub .3).sub.2HS-121 �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiC.sub. 16 H.sub.33).sub.2HS-122 Li.sub.7 HSi.sub.2 W.sub.18 Nb.sub.6 O.sub.77HS-123 Li.sub.9 P.sub.2 V.sub.3 Me.sub.3 W.sub.12 O.sub.62HS-124 Cs.sub.9 P.sub.2 V.sub.3 MeW.sub.12 O.sub.62HS-125 Cs.sub.12 P.sub.2 V.sub.3 W.sub.12 O.sub.62HS-126 K.sub.4 H.sub.2 PV.sub.4 W.sub.8 O.sub.40HS-127 Na.sub.12 P.sub.4 W.sub.14 O.sub.58HS-128 Na.sub.14 H.sub.6 P.sub.6 W.sub.18 O.sub.79HS-129 a-K.sub.5 (NbO.sub.2)SiW.sub.11 O.sub.39HS-130 K.sub.5 (TaO.sub.2)SiW.sub.11 O.sub.39HS-131 (Me.sub.3 NH).sub.5 (NbO.sub.2)SiW.sub.11 O.sub.39 Keggin PeroxoHS-132 (Me.sub.3 NH).sub.5 NbSiW.sub.11 O.sub.40 Substituted KegginHS-133 (Me.sub.3 NH).sub.5 (TaO.sub.2)SiW.sub.11 O.sub.39 Keggin PeroxoHS-134 K.sub.4 (NbO.sub.2)PW.sub.11 O.sub.39HS-135 K.sub.7 (NbO.sub.2)P.sub.2 W.sub.12 O.sub.61HS-136 (Me.sub.3 NH).sub.7 (NbO.sub.2).sub.3 SiW.sub.9 O.sub.37 Keggin PeroxoHS-137 Cs.sub.7 (NbO.sub.2).sub.3 SiW.sub.9 O.sub.37HS-138 K.sub.6 (NbO.sub.2).sub.3 PW.sub.9 O.sub.37HS-139 Na.sub.10 (H.sub.2 W.sub.12 O.sub.42)HS-140 K.sub.4 NbPW.sub.11 O.sub.40HS-141 (Me.sub.3 NH).sub.4 NbPW.sub.11 O.sub.40HS-142 K.sub.5 NbSiW.sub.11 O.sub.40HS-143 K.sub.5 TaSiW.sub.11 O.sub.40HS-144 (Me.sub.3 NH).sub.5 TaSiW.sub.11 O.sub.40 Substituted KegginHS-145 K.sub.6 Nb.sub.3 PW.sub.9 O.sub.40HS-146 K.sub.7 NbP.sub.2 W.sub.17 O.sub.62 Wells-DawsonHS-147 K.sub.7 (TiO.sub.2).sub.2 PW.sub.10 O.sub.38HS-148 K.sub.7 (TaO.sub.2).sub.3 SiW.sub.9 O.sub.37HS-149 K.sub.7 Ta.sub.3 SiW.sub.9 O.sub.40HS-150 K.sub.6 (TaO.sub.2).sub.3 PW.sub.9 O.sub.37HS-151 K.sub.6 Ta.sub.3 PW.sub.9 O.sub.40HS-152 K.sub.8 Co.sub.2 W.sub.11 O.sub.39HS-153 H.sub.2 (Me.sub.4 N).sub.4 (EtSi).sub.2 CoW.sub.11 O.sub.4OHS-154 H.sub.2 (Me.sub.4 N).sub.4 (iso-C.sub.4 H.sub.9 Si).sub.2 CoW.sub.11 O.sub.40HS-155 K.sub. 9(NbO.sub.2).sub.3 P.sub.2 W.sub.15 O.sub.59HS-156 K.sub.9 Nb.sub.3 P.sub.2 W.sub.15 O.sub.62HS-157 K.sub.12 (NbO.sub.2).sub.6 P.sub.2 W.sub.12 O.sub.56 Wells-Dawson PeroxoHS-158 K.sub.12 Nb.sub.6 P.sub.2 W.sub.12 O.sub.62 Wells-DawsonHS-159 a.sub.2 -K.sub.10 P.sub.2 W.sub.17 O.sub.61HS-160 K.sub.6 Fe(III)Nb.sub.3 P.sub.2 W.sub.15 O.sub.62HS-161 K.sub.7 Zn(II)Nb.sub.3 P.sub.2 W.sub.15 O.sub.62JM-1574 (NH.sub.4).sub.6 �a-P.sub.2 W.sub.18 O.sub.62 !.nH.sub.2 OJM-1591 K.sub.12 (H.sub.2 P.sub.2 W.sub.12 O.sub.48 !.24H.sub.2 OJM-1591A K.sub.12 �H.sub.2 P.sub.2 W.sub.12 O.sub.48 !.24H.sub.2 OJM-1605 K.sub.2 Na.sub.1.5 H.sub.4.5 (PtMo.sub.6 O.sub.24 !.8H.sub.2 OJM-1638 K.sub.6 (a.sub.2 -P.sub.2 W.sub.17 MoO.sub.62).nH.sub.2 OJM-1809A KHP.sub.2 V.sub.3 W.sub.15 O.sub.62.34H.sub.2 OJM-1819 K.sub.6 �P.sub.2 W.sub.12 Nb.sub.6 O.sub.62 !.24H.sub.2 OJM-1827 Na.sub.6 �V.sub.10 O.sub.28 !.18H.sub.2 OJM-1832 (Guanidinium).sub.8 H�PV.sub.14 O.sub.62 !.3H.sub.2 OJM-1835 K.sub.8 H�PV.sub.14 O.sub.62 !JM-1855 Na.sub.7 �MnV.sub.13 O.sub.38 !.18H.sub.2 OJM-2766 K.sub.6 �BW.sub.11 O.sub.39 Ga(OH.sub.2)!.13H.sub.2 OJM-2768 K.sub.7 H�Nb.sub.6 O.sub.19 !.13H.sub.2 OJM-2768A K.sub.7 H�Nb.sub.6 O.sub.19 !.13H.sub.2 OJM-2775 �MeN/Na/K!.sub.4 �Nb.sub.2 W.sub.4 O.sub.19 !JM-2776 �Me.sub.4 N!.sub.9 �P.sub.2 W.sub.15 Nb.sub.3 P.sub.62 !JM-2799 �Me.sub.4 N!.sub.15 �HP.sub.4 W.sub.30 Nb.sub.6 O.sub.123 !.16H.sub.2 OJM-2799A �Me.sub.4 N!.sub.15 �HP.sub.4 W.sub.30 Nb.sub.6 O.sub.123 !.16H.sub.2 OJM-2800 �Na/K!.sub.6 Nb.sub.4 W.sub.2 O.sub.19 !JM-2801 �Me.sub.4 N/Na/K!.sub.5 �Nb.sub.3 W.sub.3 O.sub.19 !.6H.sub.2 OJM-2801A �Me.sub.4 N/Na/K!.sub.5 �Nb.sub.3 W.sub.3 O.sub.19 !.6H.sub.2 OJM-2802 �Me.sub.5 CpRh).sub.4 V.sub.6 O.sub.19 !JM-2815 K.sub.5 �CpTiSiW.sub.11 O.sub.39 !.12H.sub.2 OJM-2840 b.sub.2 -K.sub.8 �SiW.sub.11 O.sub.39 !.14H.sub.2 OJM-2841 a-K.sub.8 �SiW.sub.10 O.sub.36 !.12H.sub.2 OJM-2842 Cs.sub.7 Na.sub.2 (PW.sub.10 O.sub.37).8H.sub.2 OJM-2843 Cs.sub.6 �P.sub.2 W.sub.5 O.sub.23 !.7(1/2)H.sub.2 OJM-2844 g-Cs.sub.7 �PW.sub.10 O.sub.36 !.7H.sub.2 OJM-2869 K.sub.5 �SiNbW.sub.11 O.sub.40 !.7H.sub.2 OJM-2870 K.sub.4 �PNbW.sub.11 O.sub.40 !.12H.sub.2 OJM-2871 Na.sub.6 (Nb.sub.4 W.sub.2 O.sub.19 !.13H.sub.2 OJM-2871A Na.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.20H.sub.2 OJM-2872 K.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.7H.sub.2 OJM-2873 K.sub.4 (V.sub.2 W.sub.4 O.sub.19 !.3.5H.sub.2 OJM-2874 Na.sub.5 �V.sub.3 W.sub.3 O.sub.19 !.12H.sub.2 OJM-2875 K.sub.6 �PV.sub.3 W.sub.9 O.sub.40 !.14H.sub.2 OJM-2876 Na.sub.9 �A-b-GeW.sub.9 O.sub.34 !.8H.sub.2 OJM-2877 Na.sub.10 �A-a-GeW.sub.9 O.sub.34 !.9H.sub.2 OJM-2878 K.sub.7 �BV.sub.2 W.sub.10 O.sub.40 !.6H.sub.2 OJM-2879 Na.sub.5 �CH.sub.3 Sn(Nb.sub.6 O.sub.19)!.10H.sub.2 OJM-2879A Na.sub.5 �CH.sub.3 Sn(Nb.sub.6 O.sub.19)!.10H.sub.2 OJM-2881 Na.sub.8 �Pt(P(m-SO.sub.3 Ph).sub.3).sub.3 Cl!.3H.sub.2 OJM-2882 Na.sub.3 �P(m-SO.sub.3 Ph).sub.3 !.H.sub.2 OJM-2919 (Me.sub.3 NH).sub.10 (H)�Si.sub.2 (ZrOH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 OJM-2919A (Me.sub.3 NH).sub.10 (H)�Si.sub.2 (ZrOH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 OJM-2921 K.sub.7 �A-a-GeNb.sub.3 W.sub.9 O.sub.40 !.18H.sub.2 OJM-2922 K.sub.7 �A-b-SiNb.sub.3 W.sub.9 O.sub.40 !.20H.sub.2 OJM-2923 (Me.sub.3 NH).sub.9 �A-a-HSi.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !JM-2924 (Me.sub.3 NH).sub.9 (A-a-HGe.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !JM-2925 (Me.sub.3 NH).sub.9 �A-a-HGe.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !JM-2926 K.sub.7 (H)�A-a-Ge.sub.2 Nb.sub.6 W.sub.18 O.sub.77 !.18H.sub.2 OJM-2927 K.sub.8 �A-b-Si.sub.2 Nb.sub.6 W.sub.18 O.sub.77 !JM-2928 (Me.sub.3 NH).sub.8 �A-b-Si.sub.2 Nb.sub.6 W.sub.18 O.sub.77__________________________________________________________________________ ! .sup.a NMP = Nmethylpyrrolidinone. .sup.b DMA = N,NDimethylacetamide. .sup.c HISH.sup.+ = Histidinium .sup.d LYSH.sup.+ = Lysinium .sup.e ARGH.sup.+ = Argininium .sup.f TBA = Tetrabutylammonium
Preferred polyoxometalates to be used in the present invention include HS-042, HS-053, HS-057, HS-058, HS-105, HS-106, HS-131, and HS-158. Particularly preferred are HS-058.
The present invention may be carried out by administering the polyoxomethalate directly to the lungs of the animal being treated. Preferably, the polyoxometalate is administered in the form of an aerosol.
The viral infections which may be treated by the present method include influenza A, influenza B, and RSV. Preferably, the present method is used to treat influenza A or RSV.
The present method may be used to treat respiratory viral infections in mammals such as humans, cats, horses, cows, pigs, sheep, monkeys, rabbits, rats, mice, etc., and birds such a chickens and turkeys.
Although the exact dosage of polyoxometalate to be administered will depend on the exact type, size, and condition of the animal being treated, the exact viral infection being treated, and the identity of the polyoxometalate being administered, good results are typically achieved with dosages of 0.1 to 100 mg/kg of body weight, preferably 1 to 30 mg/kg of body weight.
In certain circumstances, it may be preferred to coadminister the polyoxometalate with an additional active agent such as amantadine, rimantadine, or ribavivin. Of course, the present method may be carried out by administering a single polyoxometalate or a combination of two or more polyoxometalates.
In a preferred embodiment, the present invention provides a method for preventing respiratory viral infections. In this embodiment, the polyoxometalate is administered to a subject which has not been diagnosed as suffering from a respiratory viral infection but is considered to belong to an at risk population. With the exception of the subject to whom the polyoxometalate is administered this preventative embodiment is carried out as described above for the present method of treatment.
Examples of subjects in an at risk population to be administered polyoxometalate in the present method of prevention include subjects not yet suffering from a respiratory viral infection but in close contact with another individual, already diagnosed as suffering from a respiratory viral infection, such as a neonate or infant in a nursery in which at least one other neonate or infant has been diagnosed as suffering from a respiratory viral infection or a member of a barrack, nursing home, or school in which at least one other member has been diagnosed as suffering from a respiratory viral infection. Another at risk population is the elderly in general during flu season.
In another embodiment, the present invention provides pharmaceutical compositions which comprise a polyoxometalate for the treatment of a respiratory viral infection. Suitably, the compositions of the present invention are in a form which is conveniently administered as an aerosol spray.
The term aerosol includes compositions of matter in which particles or droplets are suspended or dispersed in a gaseous medium such a air. Thus, the term aerosol includes sprays. Apparatus and methods for forming aerosols are disclosed in Kirk-Othmer, Encyclopedia of Chemical Technology, 4th Ed., vol. 1, Wiley, New York, pp. 670-685 (1991) and Kirk-Othmer, Encyclopedia of Chemical Technology, 3rd. Ed., vol. 21, Wiley, New York, pp. 466-483 (1983), both of which are incorporated herein by reference.
The administration of the aerosol spray containing the polyoxometalate may be conveniently carried out by means of a delivery system capable of delivering an aerosol spray. Such delivery systems include conventional nasal aerosol spray bottles, or aerosol delivery via commonly used respiratory mechanical ventilation support equipment.
Typically, the present compositions will be in the form of an aqueous solution or dispersion of the polyoxometalate. The concentration of the polyoxometalate is suitably 0.1 .mu.g/ml to 10 mg/ml, preferably 10 .mu.g/ml to 1 mg/ml. The composition may further comprise a pH adjusting agent such as a physiologically tolerated acid or base, a buffer, or another active agent, such as ribavirin amantadine or rimantadine.
The present invention also provides dispensing devices for administering the present pharmaceutical compositions. Such dispensing devices comprise a container means which contains a pharmaceutical composition comprising the polyoxometalate and optionally another active ingredient; and means for forming an aerosol of the pharmaceutical composition. Suitable container means and suitable means for forming an aerosol are described in Kirk-Othmer, Encyclopedia of Chemical Technology, 4th Ed., vol. 1, Wiley, New York, pp. 670-685 (1991) and Kirk-Othmer, Encyclopedia of Chemical Technology, 3rd. Ed., vol. 21, Wiley, New York, pp. 466-483 (1983), both of which are incorporated herein by reference. Suitable container means include metal cans and glass and plastic bottles. Suitable means for forming an aerosol include combinations of propellants and valves (including an actuator and dip tube). A propellant may be present in the container under pressure, or the material in the container may be propelled by pressure created by mechanical force means such as, e.g., a bellows, bulb, or pump. Preferably, the present dispensing means is a pressurized aerosol can or an atomizer.
The present invention will now be described in more detail by referring to specific embodiments, which are not intended to be limiting.
Polyoxometalates have a broad spectrum of antimyxovirus activity. Several sulfated polysaccharides which have anionic charge inhibited adsorption of HIV, HSV, FluV-A and RSV, whereas they did not inhibit the adsorption of FluV-B, MLSV, SSPE, virus and PFluV-3 (Hosoya, M., et al, Antimicrob. Agents Chemother., vol. 35, pp. 2515-2520 (1991)). On the other hand, some polyoxometalates examined in this study had antiviral effects against FluV-A, RSV, MLSV, FluV-B, and PFluV-2. Inasmuch as the causative agents of viral respiratory infections are not rapidly identifiable by clinical diagnosis and there is a need for early treatment of patients to prevent the progress of infection, it is necessary to use a broad spectrum antiviral drug for the treatment of acute respiratory viral infections. From this point of view, HS-058 which shows a potent antiviral activity against FluV-A, FluV-B, RSV, MLSV, and PFluV-2 is especially preferred, because these viruses are the main causative agents of acute viral respiratory diseases (Hilleman, M. R., et al, J. Amer. Med. Assoc., vol. 180, pp. 444-453 (1962)).
The structure-activity relationship of polyoxometalates and antimyxoviral activity was insightful. From our examination of 25 polyoxometalates against myxoviruses, 4 compounds emerged which showed potent and broad spectrum of antiviral activity. Among them, 2 compounds HS-054 and HS-058 are so-called "sandwich structures", HS-106 is a "double Keggin structure" and HS-158 is a hexasubstituted Wells-Dawson structure. HS-054 was apparently more potent in antiviral activity and less cytotoxic than its precursor complex (HS-042). The precursor complex of HS-058 and HS-106, HS-015 (PW.sub.9 O.sub.34.sup.9 -), was not examined in this study for antimyxoviral activities but it was shown to be less effective against HIV-1 in a previous report (Hill, C. L., et al, J. Med. Chem, vol. 33, pp. 2767-2772 (1990)). The most effective compounds had Nb or Fe-base units (MO.sub.6 octahedra, M=Nb or Fe) joining two halves of the molecule.
HS-058, one of the most active polyoxometalates did not inhibit the adsorption of FluV to MDCK cells and agglutination of chick erythrocytes by FluV-A, whereas it did inhibit hemolysis of chick erythrocytes after adsorption of virus at 4.degree. C. As shown in Table 4, HS-058 did not inhibit FluV infection in MDCK cells when it was added at the time of virus adsorption (1 hour before to 1.5 hours after virus inoculation), whereas it did inhibit infection when it was present after virus adsorption for the whole course of the experiment (1 hour before to 120 hours after virus inoculation; FIG. 1 and Table 4). HS-058 was also inhibitory against FluV-A infection when it was added after virus adsorption to the end of culture (1.5 to 120 hours in Table 4). It is likely that polyoxometalates do not inhibit FluV adsorption to cellular membrane, but inhibit the fusion of the cleaved HA molecule and the cellular membrane. A similar result was reported using sulfated polysaccharides by Hosoya et al. (Hosoya, M., et al, Antimicrob. Agents Chemother., vol. 35, pp. 2515-2520 (1991)).
An insight on the mechanism of antiviral activity of HS-058 against FluV-A is apparent from the experiments on inhibition of virus replication in MDCK cells. When cells were infected with virus at a high moi and then treated with 4 EC.sub.50 of HS-058, HS-058 had no effect on the yield of infectious Flu-V relative to control. However, when cells were infected with low moi of virus and then treated with HS-058, it inhibited virus yield relative to control. Clearly, HS-058 did not inhibit the growth of infectious virus in single cells, but inhibited the spread of virus from infected to uninfected cells.
HS-058 did not inhibit the antigen synthesis and plaque formation of RSV when it was added after the virus adsorption (Tables 4 and 5, FIG. 2). In contrast to the result with FluV, HS-058 inhibited strongly RSV infection in HeLa cells when it was added during the time of virus adsorption. HS-058 inhibited syncytium formation of HeLa cells by RSV infection. It appears that the antiviral mechanism of the polyoxometalate HS-058 occurs at two important points during virus-cell interactions. The first is adsorption of RSV to cell membrane and penetration (hemolysis) of FluV-A into cells. The second point is the late stage of virus infection by inhibiting cell-to-cell spread of RSV and FluV-A.
Of note was the recognition that several of the polyoxometalates which exhibited selective anti-HIV-1 activity were also potent antiviral agents against FluV-A (Table 2). This parity was not as strong with RSV or MLSV. HS-058 is a compound with modest anti-HIV-1 activity comparable to 2', 3'-dideoxyinosine, a compound approved for the treatment of HIV.
The present invention also provides a method for treating human herpes virus infection by administering a polyoxometalate. In the context of the present invention, the term human herpes virus infection includes not only herpes simplex virus type 1 but also herpes simplex virus type 2 and cytomegalovirus. The present method specifically includes the treatment of herpes simplex virus type 1 (HSV-1), herpes simplex virus type 2 (HSV-2), cytomegalovirus (CMV), Epstein-Barr virus (EPV), human herpes virus type 6 (HHV-6), human herpes virus type 7 (HHV-7), and human herpes virus type 8 (HHV-8). The preferred mode of administration for HSV-1, and HSV-2 is topical administration in the form of a cream containing 0.1 to 5% by weight, based on the total weight of the cream, of the polyoxometalate. In addition, the polyoxometalate may be administered systemically. For the other human herpes virus infections, systemic administration is preferred, more preferably intravenous administration. The dosage range for the treatment of herpes virus infection is the same as that used for the treatment of respiratory viral infection discussed above.
In another embodiment, the present invention provides a method for treating hepadnavirus infection, in particular hepatitis B virus (HBV), by administering a polyoxometalate. In this case, systemic administration is preferred, more preferably intravenous administration. Again, the dosage ranges for the treatment of hepadnavirus infection are the same as discussed above for the respiratory viral infection treatment.
In the case of treating herpes virus infection, and hepadnavirus infection, it is not only possible to use the polyoxometalate compounds discussed above, but in addition, it is possible to use the polyoxometalate compounds discussed in Ikeda et al, Antiviral Chemistry & Chemotherapy, vol. 4, pp. 253-262 (1993), which is incorporated herein by reference in its entirety.
Other features of the invention will become apparent in the course of the following descriptions of exemplary embodiments which are given for illustration of the invention and are not intended to be limiting thereof.
EXAMPLES
MATERIALS AND METHODS
Chemicals. Twenty five compounds were submitted to the antiviral assay (see Table 1 above) and synthesized according to the procedures which are published elsewhere. (Droege, M. W., et al, J. Mol. Catal., vol. 69, p. 323 (1991); Finke, R. G., et al, J. Am. Chem. Soc., vol. 106, pp. 7274-7277 (1984); Finke, R. G., et al, Inorg, Chem., vol. 26, pp. 3886-3896 (1987); Hill, C. L., et al, J. Med. Chem., vol. 33, pp. 2767-2772 (1990); Hill, C. L., et al, in Advances in Chemotheraly of AIDS, Diasio, R. B. et al, Eds., Pergamon Press, New York, pp. 33-41 (1990); Kim, G. S., et al, J. Med. Chem., vol. 37, pp. 816-820 (1994); Kim, G. S., et al, unpublished work; Lyon, D. K., et al, J. Am. Chem. Soc., vol. 113, pp. 7209-7221 (1991), Weeks, M. S., et al, J. Med. Chem., vol. 35, pp. 1216-1221 (1992)). Dextran sulfates were purchased from Sigma Chemical Co. (St. Louis, Mo.).
Virus and cells. FluV, A/Ishikawa/7/82 (H3N2) and B/Singapore/222/79 had been passed more than 20 times in embryonated eggs. Both viruses were passed twice in Madin-Darby canine kidney (MDCK) cells before being used for virus growth or growth inhibition experiments in MDCK cells. RSV Long strain (type-A) had been passed in HEp-2 cells more than 20 times. Fresh isolates of RSV FM-58-8 (type-A) and SM-61-48 (type-B) were passed 5 times in HEp-2 cells after isolation. Measles virus (MLSV) Edmonston strain, mumps virus (MPSV) ECXH-3 strain, parainfluenzavirus (PFluV) type 2, Greer strain and (PFluV) type 3, C243 strain were passed 10 times in Vero cells, and MLSV, MPSV, and PFluV-2 were passed an additional 3 times in HMV-2 cells (Nishimura, H. K., et al, J. Gen. Virol., vol. 70, pp. 1653-1661 (1989)). Sources of virus strains and culture cell lines used for studies with the myxo viruses have been reported previously (Shigeta, S., et al, Antiviral Chem. Chemother., vol. 3, pp. 171-177 (1992); Shigeta, S., et al, Antimicrob. Agents Chemother., vol. 36, pp. 435-439 (1992)).
MDCK, HEp-2, HMV-2 and Vero cells were cultured in Eagle's minimal essential medium (MEM) supplemented with 10% newborn calf serum, 100 units of penicillin G, and 100 mg of streptomycin per ml. For the infections of HEp-2 cells with RSV, HMV-2 cells with any of MLSV, MPSV and PFluV-2 and Vero cells with PFluV-3, a maintenance medium consisting of MEM with 2% heat-inactivated fetal calf serum and antibiotics was used. For the infection of MDCK cells with FluV, a maintenance medium consisting of MEM containing 0.2% bovine albumin, 2.5 .mu.g/ml of crystallized trypsin (Sigma Chemical Co., St. Louis, Mo.) and antibiotics was used. For the plaque assay of RSV, HeLa cells grown in MEM supplemented with 10% newborn calf serum, 1.6% glucose and antibiotics, and MM consisting of MEM with 2% fetal calf serum, 1.6% glucose, antibiotics and 0.7% methyl cellulose (Methocel A-4M Premium; Dow Chemical Co. Midland, MI) were used.
Antiviral assay. Antimyxovirus evaluation was principally followed the MTT assay by Pauwels et al. (Pauwels, R., et al, J. Virol. Meth., vol. 20, pp. 309-321 (1988)). Four-fold dilution of compound (100 .mu.l) was prepared in a 96 well tissue culture tray (Nunclon, 96 wells, Nunc A/S, Roskilde, Denmark) with 4 wells each for one dilution and combined with 10.sup.4 cells (50 .mu.l) and 100 TCID.sub.50 of virus (50 .mu.l). The tray was centrifuged at 700 g for 5 minutes and incubated at 35.degree. C. for 4 to 5 days. During the incubation, the culture medium with or without compound was changed after 3 days. To determine the median effective antiviral concentration (EC.sub.50), we added 20 ml of 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) at a concentration of 7 .mu.g/ml in phosphate buffered saline (PBS, pH 7.2) to each well of cultures. The mixture was incubated at 37.degree. C. for 2 hours and reduced MTT (formazan) was extracted by adding 100 .mu.l of acidic isopropanol containing 4% Triton-X. The absorbance of blue color of formazan was measured using a computer controlled microplate reader (Model 3550, Bio Rad, Hercules, Calif.) at two different wavelengths (540 and 690 nm). The EC.sub.50 was expressed as the concentration that achieved the 50% protection of virus infected cells from the virus induced destruction. The percent protection was calculated by the following formula:
�(OD.sub.T)V-(OD.sub.C)V!/�(OD.sub.C)M-(OD.sub.C)V!.times.100(%),
where (OD.sub.T)V, (OD.sub.C)V and (OD.sub.C)M indicate the absorbance of the test sample, the virus infected control (no compound), and the mock infected control (no virus and no compound), respectively.
Antiviral activity against RSV was examined by a plaque reduction method. Monolayer cultures of HeLa cells were treated with 4-fold dilution of compound and infected with 50 plaque forming units (PFU) of virus. Virus and compound were diluted in maintenance media containing 0.7% methylcellulose. Infected cultures were incubated at 35.degree. C. for 4 days, fixed with 5% formalin in PBS, stained with 0.02% crystal violet and the number of plaque in monolayer was counted under a microscope (40.times. magnification). The concentration of compound which reduced the number of plaques to 50% of the control was determined as the EC.sub.50.
The anti-HIV-1 activity of the compounds was determined in human PBM cells as described previously (Schinazi, R. F., et al, Antimicrob. Agents Chemother., vol. 36, pp. 2423-2431 (1992)). Sterile stock solutions (40 mM) of the new compounds were prepared in water and then diluted to the desired concentration in medium. Cells were infected with the prototype HIV-1.sub.LAl at a multiplicity of infection of 0.01. Virus obtained from the cell supernatant was quantitated on day 6 after infection by a reverse transcriptase assay using poly(rA).sub.n. oligo(dT).sub.12-18 as template-primer. Studies have indicated a strong correlation (r.sup.2 .gtoreq.0.88) between results obtained using the reverse transcriptase assay and a commercial HIV-1 p24 assay for polyoxometalates. The toxicity of the compounds was assessed in human PBM cells, as described previously (Schinazi, R. F., et al, Antimicrob. Agents Chemother., vol. 36, pp. 2423-2431 (1992)). The EC.sub.50 and median inhibitory concentration (IC.sub.50) were obtained from the concentration-response curve using the median effective method described by Chou and Talalay (Chou, T. C., et al, Adv. Enzyme Regul., vol. 22, pp. 27-55 (1984)).
Immunofluorescent staining of RS virus infected cells. HeLa cells were seeded in Lab-Tek chamber slide (8 chambers, Nunc Inc. Naperville, Ill.) and incubated at 37.degree. C. in 5% CO.sub.2. When the cell monolayer became confluent, approximately 50 PFU of RSV was inoculated in each well of the chamber. The cultures were incubated at 35.degree. C. in a 5% CO.sub.2 incubator. At 48 hours after infection, the maintenance media was removed, the cells were washed with PBS (pH, 7.2), and fixed with acetone for 10 minutes at room temperature. The fixed cells were stained with fluorescein isothiocyanate conjugated rabbit antibodies against RSV (Denka Seiken Co., Niigata, Japan) for 30 minutes at 37.degree. C., mounted with 20% glycerol in PBS, and analyzed for immunofluorescence under a fluorescent microscope (Nikon Optiphot+EFD2, Nikon Industrial Co., Tokyo, Japan). Inhibitory effects of the compounds on RSV antigen synthesis and syncytium formation were monitored by counting the number of antigen positive foci or cells in a syncytium after immunofluorescent staining of infected cells. The details for the immunofluorescence for RSV were reported elsewhere (Shigeta, S., et al, Antiviral Chem. Chemother., vol. 3, pp. 171-177 (1992)).
Hemagglutination, hemolysis by influenzavirus, and inhibition assay. Fresh FluV-A was obtained from allantoic fluid of infected embryonated chicken egg. The virus was 2-fold diluted with PBS (pH 7.2), 100 .mu.l distributed each to wells of a microtray, combined with the same volume of 0.5% fresh chicken erythrocytes, and was left at 4.degree. C. for 1 hour. Titer of hemagglutinin (HA) of the virus was determined as 256 units/100 .mu.l. After the hemagglutination, erythrocytes were centrifuged at 700 g for 5 minutes, resuspended in fresh 0.1M sodium acetate buffer solution (pH, 5.25), and incubated at 37.degree. C. for 30 minutes. The procedure reported by Huang et al (Huang, R. T. C., et al., Virology, vol. 110, pp. 243-247 (1981)) for hemolysis studies by FluV-A was followed. Maximum hemolysis was determined by absorbency at 540 nm which measures hemoglobin. For the inhibition of hemagglutination by the compounds, 2-fold dilutions of compound in PBS (pH 7.2) (100 .mu.l), and 4 HA units of FluV-A (100 .mu.l) were combined with 0.5 % chick erythrocytes (200 .mu.l), and the mixture was left at 4.degree. C. for 1 hour. The minimal concentration of compound which inhibited hemagglutination was determined as the minimal inhibitory dose (MID). For the inhibition of hemolysis, chick erythrocytes were agglutinated in several wells of a microtray by 100 units of HA following the procedure above. After hemagglutination, buffer was replaced with 2-fold dilution of compound in acetate buffer solution (pH 5.25), and the mixture was incubated at 37.degree. C. for 30 minutes. The minimal concentration of compound which reduced the absorbance at 540 nm by 50% of control was defined as the EC.sub.50.
RESULTS
Antiviral activities of several polyoxometalates against ortho- and paramyxoviruses. Twenty-five compounds (see Table 1 above) were evaluated for their inhibitory activities on the cytopathic effect of FluV-A, RSV and MLSV in tissue culture cells by MTT method. Among the compounds examined, 24 demonstrated antiviral activity against FluV-A, 11 showed activity against RSV, and 6 were effective against MLSV at lower concentrations than the cytotoxicity to each host cell (see Tables 2 and 3). Among the effective compounds. HS-054 or �Na.sub.16 Fe.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2. nH.sub.2 O! (Wells-Dawson sandwich structure), HS-058 or �K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O! (Keggin sandwich structure), HS-106 or �(Me.sub.3 NH).sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O! (double Keggin structure), and HS-158 or (K.sub.12 Nb.sub.6 P.sub.2 W.sub.12 O.sub.62) (hexasubstituted Wells-Dawson structure) exhibited potent and broad-spectrum antimyxovirus activities. These 4 compounds were further examined for antiviral activities against 9 myxovirus strains including an additional 6: FluV-B, MPSV, PFluV-2, PFluV-3, RSV-A, and RSV-B. Two RSV strains were fresh isolates from patients. The results shown in Table 3 indicate that FluV-A, FluV-B, RSV, MLSV, and PFluV-2 were susceptible to all 4 compounds at concentrations from 0.3 to 45.7 .mu.M. On the other hand, MPSV and PFluV-3 were susceptible only to HS-054 at relatively high concentrations (21 to 28 .mu.M). HS-058 showed EC.sub.50 values of 1.4 .mu.M against FluV-A, 13.9 .mu.M against FluV-B, 5.6 .mu.M against RSV (Long strain), 0.8 .mu.M against MLSV and 0.43 .mu.M against PFluV-2. HS-058 was not inhibitory for MPSV and PFluV-3 at 50 .mu.M. HS-058 and HS-106 were less cytotoxic to MDCK and HEp-2 cells than HS-054 and HS-158, but more toxic to HMV-2 cells than the latter cell lines. HS-058 was not cytotoxic up to 200 .mu.M for MDCK and HEp-2 cells, but had an IC.sub.50 value of 50 .mu.M for HMV-2 and Vero cells.
TABLE 2__________________________________________________________________________ANTIVIRAL ACTIVITY OF POLYOXOMETALATESFOR MYXOVIRUSES AND HIV-1 IN VITRO Antiviral activity, EC.sub.50 .mu.M Cytotoxicity, IC.sub.50 .mu.MCompound FLuV-A RSV MLSV HIV-1 MDCK HEp-2 HMV-2 PBM__________________________________________________________________________HS-005 1.8.sup.a 1.9 1.5 0.4 50 1.9 26.0 35.0HS-008 6.3 >50 >43 0.3 >100 50.0 43.0 >100HS-010 1.2 0.9 1.9 0.9 >100 12.4 30.0 1.8HS-026 0.23 >1.1 >3.7 0.3 16.0 1.1 3.9 7.7HS-042 2.7 >8.6 >16.2 4.7 >100 8.6 20.4 >100HS-052 0.9 >2.7 >0.8 0.1 >100 2.7 1.0 39.2HS-053 1.1 1.4 >28.1 0.3 100 >50 25.6 4.5HS-054 0.7 1.4 0.2 0.4 >100 >50 >50 20.8HS-055 2.0 >26 >16 1.6 100 26.0 22.0 91.5HS-056 21.1 >22 >1.6 4.5 50 22.0 1.8 93.1HS-057 1.1 >50 20.6 1.3 100 >50 31.0 >100HS-058 1.1 3.8 0.76 1.7 >100 >50 50.0 >100HS-083 >35 >9.3 23.6 36.2 35.2 9.3 31.0 >100.sup.bHS-089 11.2 >3.7 >50 51.5 71.7 37.0 50.0 >100.sup.bHS-091 3.8 1.6 >80 0.2 50.0 6.2 8.0 5.9.sup.bHS-105 5.0 4.5 >50 0.6 100 >50 >50 >100.sup.bHS-106 3.6 >9.3 >50 0.3 100 9.3 >50 >100.sup.bHS-131 2.5 9.2 >50 0.8 85.6 47.1 50.0 >100.sup.bHS-132 13.4 7.8 >50 0.8 >100 50.0 50.0 >100.sup.bHS-133 4.0 5.1 >10 1.4 100 >50 27.0 >100.sup.bHS-136 10.0 >50 >50 2.0 100 >50 >50 >100.sup.bHS-144 11.4 7.3 29 0.2 >100 >50 37.6 >100.sup.bHS-146 2.2 1.0 >4.5 0.2 56.6 8.0 12.8 49.7.sup.bHS-157 2.1 11.6 >50 0.1 100 11.6 >50 58.4.sup.bHS-158 1.5 >10 1.2 0.3 >100 10.0 44.2 75.0.sup.bRibavirin 8.7 4.7 5.2 NA >100 >50 >100 NA__________________________________________________________________________ .sup.a Underline indicates that the effective antiviral concentration is at least 10fold below the cytotoxic concentration. The variance for duplicate or triplicate assays was less than 15%. .sup.b Cytotoxicity determined by 3Hthymidine uptake instead of cell proliferation.
TABLE 3__________________________________________________________________________INHIBITORY EFFECTS OF 4 POLYOXOMETALATES AGAINSTSEVERAL ORTHO- AND PARAMYXOVIRUSES EC.sub.50.sup.a and IC.sub.50 of Polyoxometalates, .mu.MVirus strain HS-054 HS-058 HS-106 HS-158 Ribavirin__________________________________________________________________________Antiviral ActivityFLuV-A 0.59 1.4 2.8 2.8 3.7(Ishikawa) (0.37-0.94) (0.7-2.0) (1.3-5.4) (1.0-5.5) (1.8-7.0)FLuV-B 35.5 13.9 45.7 36.5 5.1(Singapore) (20-54) (8.7-21.8) (19.4-68) (30-43) (1.8-5.2)RSV-A 2.8 5.6 9.8 14.2 4.7(Long) (1.4-4.5) (2.4-13.5) (9.0-10.3) (8.3-24.4) (1.5-9.7)RSV-A 5.0.sup.b 23.0 10.0 8.5 3.5(FM-58-8)RSV-B 7.6.sup.b 3.1 4.5 2.7 1.6(SM61-48)MLSV 0.3 0.8 6.6 1.4 5.2(Edmonston) (0.2-0.4) (0.76-0.85) (5.6-7.6) (1.23-1.61) (1.9-10.0)MPSV 20.6 >50 >50 >50 3.4(EXCH-3) (15.5-20) (3.1-37.1)PFLuV-2 1.8 0.43 7.8 24.1 8.9(Greer) (1.5-2.1) (0.32-0.54) (2.6-16.1) (23.2-25.0) (6.4-11.2)PFLuV-3 28.0 >50 >50 >50 17.2(C243) (25-31) (16.4-18.0)Cytotoxicity.sup.cMDCK >200 >200 >200 164 >200 (>200).sup.c (>200) (200) (166) (>200)HEp-2 88 >200 >200 82.7 52.7 (38.0) (80.5) (192.2) (69.4) (>200)HMV-2 >200 50 20.7 53.7 >100 (94.1) (52.2) (70.7) (73.1) (>100)Vero 50 50 148 >200 100 (37.5) (38.4) (>200) (41.4) (>200)__________________________________________________________________________ .sup.a Average of 3 to 4 independent experiments. Numbers in parentheses show the range of values. .sup.b Data from one experiment. .sup.c IC.sub.60 was examined by MTT method and viable cell counting. The data in parentheses indicate the results of viable cell counting.
Antiviral effect of HS-058 added before, during, and after virus adsorption.
In order to analyze the mechanism of antiviral activity of HS-058 against FluV-A and RSV, the compound was added to host cells before, during, and after virus infection. For the antiviral assay against FluV-A, MDCK cells were used and examined by MTT assay. For the assay against RSV, HeLa cells monolayers were used and examined by a plaque reduction method. As shown in Table 4, when HS-058 was added to the culture at 1 hour before the virus inoculation and maintained throughout the experiment, it was inhibitory against FluV-A at less than 0.7 .mu.M and against RSV at 2.0 .mu.M. When HS-058 was added to the culture 1 hour before and removed from the culture 1.5 hours after the virus inoculation, it was inhibitory against RSV at 2.4 .mu.M, but was not inhibitory against FluV-A. When the compound was added after the virus adsorption (at 1.5 hour) and removed 3 hours after infection it was not inhibitory against both FluV-A and RSV. On the other hand, when the compound was added after virus adsorption and maintained throughout the experiment, it was inhibitory against both viruses at 4.1 and 5.8 .mu.M (Table 4).
TABLE 4______________________________________TIME OF ADDITION AND INHIBITORY EFFECTSOF HS-058 ON INFLUENZA AND RESPIRATORYSYNCYTIAL VIRUS REPLICATIONS.Time of addition EC.sub.50 (.mu.M) against:of compound (hours).sup.a FluV-A(Ishikawa) RSV(Long)______________________________________-1 to 120 0.7 2.0-1 to 1.5 >20 2.41.5 to 120 4.1 5.81.5 to 3 >31 >20______________________________________ .sup.a Time of addition before or after virus inoculation. Cells were washed extensively after removal of compound.
Inhibitory effect of HS-054 and HS-058 against hemagglutination and hemolysis of chick erythrocytes by influenza virus type A. FluV-A binds to chick erythrocytes membrane at 4.degree. C. in neutral buffered solution and hemolysis occurs at 37.degree. C. in weakly acidic solution. The inhibitory effect of HS-054 and HS-058 against hemagglutination by 4 units of viral-HA and hemolysis by 100 units of viral-HA was examined. As shown in Table 5, both compounds did not inhibit hemagglutination at 100 .mu.M, but inhibited hemolysis at 80 and 58 .mu.M, respectively. On the other hand, dextran sulfates did not inhibit hemagglutation and hemolysis at all.
TABLE 5______________________________________INHIBITORY EFFECTS OF HS-058 FOR HEMAGGLUTINATION,HEMOLYSIS OF INFLUENZA VIRUS AND ANTIGEN SYNTHESIS,SYNCYTIUM FORMATION OF RESPIRATORY SYNCYTIAL VIRUS Anti-FluV-A activity (.mu.M) Anti-RSV activity (.mu.M) Inhibition for: Inhibition for:Compound HA Hemolysis Antigen Syncytium______________________________________HS-054 >200 80(56-88).sup.a >200.sup. 3.6(2.5-4.2)HS-058 >200 58(350-81).sup.a >200.sup. 8.5(6.5-13)DS-8000.sup.b >200 >200.sup.c >200.sup.c >200.sup.cDS-50000.sup.b >200 >200.sup. >200.sup.c >200.sup.c______________________________________ .sup.a Average of 2 to 3 independent experiments. Numbers in parentheses show range of value. .sup.b Molecular weights of dextran sulfates. .sup.c Concentrations are expressed as .mu.g/ml.
Inhibitory effect of HS-054 and HS-058 against syncytium formation by respiratory syncytial virus. The inhibitory effect of HS-054 and HS-058 against syncytium formation of RSV in HeLa cell monolayers was examined by immunofluorescence. Both compounds inhibited syncytium formation of HeLa cells by RSV at 3.6 and 8.5 .mu.M, respectively, but did not inhibit viral specific antigen synthesis at 100 .mu.M (Table 5 and FIG. 2). Dextran sulfates did not inhibit antigen synthesis and syncytium formation at 100 .mu.M.
Inhibitory effect of HS-058 on one step growth of FluV-A in MDCK cells. A 2-day culture of MDCK cells with confluent monolayer cells was prepared in 50 ml Nunclon tissue culture plates. Two sets of virus infected cultures were prepared. One set was infected with a high moi (5.0) and the other with a low moi (0.005). Both sets included virus control cultures which did not contain HS-058 throughout the experiment. Experimental cultures were treated with 4.4.times.EC.sub.50 of the compound (6.0 .mu.M) before (60 min) and after (90 min) virus inoculation while maintaining the compound throughout the culture period. Four to five flasks, prepared for each control and experimental cultures, were sampled at the time indicated in FIG. 1. The flasks were frozen at -80.degree. C., thawed at 37.degree. C., centrifuged at 700 g for 10 min and then titrated for yield of infectious virus in the supernatant. As shown in FIG. 1a, in the culture infected with high moi, HS-058 inhibited virus replication when added to cultures before virus adsorption, but was not inhibitory when added after virus adsorption to cells. In contrast, HS-058 inhibited virus yield production when the culture was infected with virus at a low moi, even when the compound was added after virus adsorption. These results indicate that the compound inhibits the virus adsorption and also cell-to-cell spread of virus.
Anti-HIV-1 activity in human lymphocytes. Of the 25 compounds evaluated in acutely infected primary human PBM cells, 23 compounds demonstrated activity below 5 .mu.M (Table 2). HS-008, HS-106, and HS-144 had a selectivity index greater than 300 and had no cytotoxicity to uninfected PBM cells when evaluated up to 100 .mu.M. HS-058 was a modest inhibitor of HIV-1 with an EC.sub.50 of 1.7 .mu.M and no apparent cytotoxicity in any of the 4 different cells used.
Obviously, numerous modifications and variations of the present invention are possible in light of the above teachings. It is therefore to be understood that, within the scope of the appended claims, the invention may be practiced otherwise than as specifically described herein.
Claims
  • 1. A method for treating an animal suffering from respiratory viral infection, comprising administering to said animal an effective amount of a polyoxometalate, wherein said respiratory viral infection is selected from the group consisting of influenza A, influenza B, and RSV and said polyoxometalate is selected from the group consisting of
  • �(NMP).sub.2 H!.sub.3 PW.sub.12 O.sub.40
  • �(DMA).sub.2 H!.sub.3 PMo.sub.12 O.sub.40
  • (NH.sub.4).sub.17 Na�NaSb.sub.9 W.sub.21 O.sub.86 !
  • a- and b-H.sub.5 BW.sub.12 O.sub.40
  • a- and b-H.sub.6 ZnW.sub.12 O.sub.40
  • a- and b-H.sub.6 P.sub.2 W.sub.18 O.sub.62
  • .alpha.-(NH.sub.4).sub.6 P.sub.2 W.sub.18 O.sub.62
  • K.sub.10 Cu.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H.sub.2 O
  • K.sub.10 Co.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H.sub.2 O
  • Na.sub.7 PW.sub.11 O.sub.39
  • Na.sub.7 PW.sub.11 O.sub.39.20H.sub.2 O+2 C.sub.6 H.sub.5 P(O)(OH).sub.2
  • (n-Bu.sub.4 N).sub.4 H.sub.3 PW.sub.11 O.sub.39
  • b-Na.sub.8 HPW.sub.9 O.sub.34
  • (n-Bu.sub.4 N).sub.3 PMoW.sub.11 O.sub.39
  • a-�(nBu).sub.4 N!.sub.4 Mo.sub.8 O.sub.26
  • (n-Bu.sub.4 N).sub.2 W.sub.6 O.sub.19
  • (n-Bu.sub.4 N).sub.2 Mo.sub.6 O.sub.19
  • a-(NH.sub.4).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • a-(NH.sub.4).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • a-K.sub.5 BW.sub.12 O.sub.40
  • K.sub.4 W.sub.4 O.sub.10 (O.sub.2)6
  • b-Na.sub.9 HSiW.sub.9 O.sub.34
  • Na.sub.6 H.sub.2 W.sub.12 O.sub.40
  • (NH.sub.4).sub.14 �NaP.sub.5 W.sub.30 O.sub.110 !
  • a-(NH.sub.4).sub.5 BW.sub.12 O.sub.40
  • a-Na.sub.5 BW.sub.12 O.sub.40
  • (NH.sub.4).sub.4 W.sub.10 O.sub.32
  • (Me.sub.4 N).sub.4 W.sub.10 O.sub.32
  • (HISH.sup.+).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • (LYSH.sup.+).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • (ARCH.sub.+).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • (HISH.sub.+).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • (LYSH.sup.+).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • (ARGH.sup.+).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • a-K.sub.8 SiW.sub.11 O.sub.39
  • a-K.sub.8 SiW.sub.11 O.sub.39
  • K.sub.10 (H.sub.2 W.sub.12 O.sub.42 )
  • K.sub.12 Ni.sub.3 (II)(PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • (NH.sub.4).sub.10 Co.sub.4 (II)(PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 Pd.sub.3 (II)(PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • Na.sub.12 P.sub.2 W.sub.15 O.sub.56.18H.sub.2 O
  • Na.sub.16 Cu.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Zn.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Co.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Ni.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Mn.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56) .nH.sub.2 O
  • Na.sub.16 Fe.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • K.sub.10 Zn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H.sub.2 O
  • K.sub.10 Ni.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.10 Mn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 Cu.sub.3 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 (Co H.sub.2 O).sub.3 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 Zn.sub.3 (PW.sub.9 O.sub.34).sub.2.15H.sub.2 O
  • K.sub.12 Mn.sub.3 (PW.sub.9 O.sub.34).sub.2.15H.sub.2 O
  • K.sub.12 Fe.sub.3 (PW.sub.9 O.sub.34).sub.2.25H.sub.2 O
  • (ARGH.sup.+).sub.10 (NH.sub.4).sub.7 Na�NaSb.sub.9 W.sub.21 O.sub.86 !
  • (ARGH.sup.+).sub.5 HW.sub.11 O.sub.39.17H.sub.2 O
  • K.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • �(CH.sub.3).sub.4 N!.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • Cs.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • �HISH+!.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • (LYSH+).sub.n Na.sub.7-n PTi.sub.2 W.sub.10 O.sub.40
  • (ARGH+).sub.n Na.sub.7-n PTi.sub.2 W.sub.10 O.sub.40
  • Cs.sub.4 �SiW.sub.11 O.sub.39.O(SiCH.sub.2 CH.sub.2 C(O)OCH.sub.3).sub.2 !.sub.4 --
  • �TBA!.sub.3 H.sub.3 V.sub.10 O.sub.28
  • K.sub.7 HNb.sub.6 O.sub.19.13H.sub.2 O
  • K.sub.8 Ta.sub.6 O.sub.19.17H.sub.2 O
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O (SiCH.sub.2 CH.sub.2 C(O)OCH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl)
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl)
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 -(SiCH=CH.sub.2)
  • Cs.sub.4 �SiW.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 CN).sub.2 !
  • Cs.sub.4 �SiW.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl).sub.2 !
  • Cs.sub.4 �SiW.sub.11 O.sub.39 -(SicH=CH.sub.2).sub.2 !
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 O(SiCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub.2 CH.sub.2 CH.sub.2 CN).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 --O(SiCH.dbd.CH.sub.2).sub.2
  • �(CH.sub.2).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 --O(SiC(CH.sub.3).sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 --O(SiCH.sub.2 CH(CH.sub.3).sub.2).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.3 PW.sub.11 O.sub.39 O(SiCH.sub.2 CH.sub.2 COOCH.sub.3).sub.2
  • K.sub.5 Mn(II)PW.sub.11 O.sub.39 --nH.sub.2 O
  • K.sub.8 Mn(II)P.sub.2 W.sub.17 O.sub.61.nH.sub.2 O
  • K.sub.6 Mn(II)SiW.sub.11 O.sub.39.nH.sub.2 O
  • K.sub.5 PW.sub.11 O.sub.39 (SiMe.sub.2).nH.sub.2 O
  • K.sub.3 PW.sub.11 O.sub.41 (PPh).sub.2.xH.sub.2 O
  • Na.sub.3 PW.sub.11 O.sub.41 (PPh).sub.2.xH.sub.2 O
  • K.sub.5 PTiW.sub.11 O.sub.40
  • Cs.sub.5 PTiW.sub.11 O.sub.39
  • K.sub.6 SiW.sub.11 O.sub.39 (SiMe.sub.2).nH.sub.2 O
  • K.sub.3 PW.sub.11 O.sub.41 (PEt).sub.2.nH.sub.2 O
  • KSiW.sub.11 O.sub.39 �SiPh(t-BU)!.nH.sub.2 O
  • K.sub.6 SiW.sub.11 O.sub.39 (SiPh.sub.2).nH.sub.2 O
  • K.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • Cs.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • Cs.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • (Me.sub.3 NH).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • (CN.sub.3 H.sub.6).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • (CN.sub.3 H.sub.6 .sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • Rb.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • Rb.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • K.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • K.sub.6 P.sub.2 Mo.sub.18 O.sub.62.nH.sub.2 O
  • (C.sub.5 H.sub.5 N).sub.7 HSi.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • (C.sub.5 H.sub.5 N).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • (ARGH.sup.+).sub.8 SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 O
  • (LYSH.sup.+).sub.7 K SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 O
  • (HISH.sup.+).sub.6 K.sub.2 SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 O
  • H.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O (2 batches)
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub.2 CH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiC.sub.16 H.sub.33).sub.2
  • Li.sub.7 HSi.sub.2 W.sub.18 Nb.sub.6 O.sub.77
  • Li.sub.9 P.sub.2 V.sub.3 Me.sub.3 W.sub.12 O.sub.62
  • Cs.sub.9 P.sub.2 V.sub.3 Mew.sub.l2 O.sub.62
  • Cs.sub.12 P.sub.2 V.sub.3 W.sub.12 O.sub.62
  • K.sub.4 H.sub.2 PV.sub.4 W.sub.8 O.sub.40
  • Na.sub.12 P.sub.4 W.sub.14 O.sub.58
  • Na.sub.14 H.sub.6 P.sub.6 W.sub.18 O.sub.79
  • a-K.sub.5 (NbO.sub.2)SiW.sub.11 O.sub.39
  • K.sub.5 (TaO.sub.2)SiW.sub.11 O.sub.39
  • (Me.sub.3 NH).sub.5 (NbO.sub.2)SiW.sub.11 O.sub.39
  • (Me.sub.3 NH).sub.5 NbSiW.sub.11 O.sub.40
  • (Me.sub.3 NH).sub.5 (TaO.sub.2) SiW.sub.11 O.sub.39
  • K.sub.4 (NbO.sub.2)PW.sub.11 O.sub.39
  • K.sub.7 (NbO.sub.2)P.sub.2 W.sub.12 O.sub.61
  • (Me.sub.3 NH).sub.7 (NbO.sub.2).sub.3 SiW.sub.9 O.sub.37
  • Cs.sub.7 (NbO.sub.2).sub.3 SiW.sub.9 O.sub.37
  • K.sub.6 (NbO.sub.2).sub.3 PW.sub.9 O.sub.37
  • Na.sub.10 (H.sub.2 W.sub.12 O.sub.42)
  • K.sub.4 NbPW.sub.11 O.sub.40
  • (Me.sub.3 NH).sub.4 NbPW.sub.11 O.sub.40
  • K.sub.5 NbSiW.sub.11 O.sub.40
  • K.sub.5 TaSiW.sub.11 O.sub.40
  • (Me.sub.3 NH).sub.5 TaSiW.sub.11 O.sub.40
  • K.sub.6 Nb.sub.3 PW.sub.9 O.sub.40
  • K.sub.7 NbP.sub.2 W.sub.17 O.sub.62
  • K.sub.7 (TiO.sub.2).sub.2 PW.sub.10 O.sub.38
  • K.sub.7 (TaO.sub.2).sub.3 SiW.sub.9 O.sub.37
  • K.sub.7 Ta.sub.3 SiW.sub.9 O.sub.40
  • K.sub.6 (TaO.sub.2).sub.3 PW.sub.9 O.sub.37
  • K.sub.6 Ta.sub.3 PW.sub.9 O.sub.40
  • K.sub.8 Co.sub.2 W.sub.11 O.sub.39
  • H.sub.2 (Me.sub.4 N).sub.4 (EtSi).sub.2 CoW.sub.11 O.sub.40
  • H.sub.2 (Me.sub.4 N).sub.4 (iso-C.sub.4 H.sub.9 Si).sub.2 CoW.sub.11 O.sub.40
  • K.sub.9 (NbO.sub.2).sub.3 P.sub.2 W.sub.15 O.sub.59
  • K.sub.9 Nb.sub.3 P.sub.2 W.sub.15 O.sub.62
  • K.sub.12 (NbO.sub.2).sub.6 P.sub.2 W.sub.12 O.sub.56
  • K.sub.12 Nb.sub.6 P.sub.2 W.sub.12 O.sub.62
  • a.sub.2 -K.sub.10 P.sub.2 W.sub.17 O.sub.61
  • K.sub.6 Fe(III)Nb.sub.3 P.sub.2 W.sub.15 O.sub.62
  • K.sub.7 Zn(II)Nb.sub.3 P.sub.2 W.sub.15 O.sub.62
  • (NH.sub.4).sub.6 �a-P.sub.2 W.sub.18 O.sub.62 !.nH.sub.2 O
  • K.sub.12 �H.sub.2 P.sub.2 W.sub.12 O.sub.48 !.24H.sub.2 O
  • K.sub.12 �H.sub.2 P.sub.2 W.sub.12 O.sub.48 !.24H.sub.2 O
  • K.sub.2 Na.sub.1.5 H.sub.4.5 (PtMo.sub.6 O.sub.24 !.8H.sub.2 O
  • K.sub.6 �a.sub.2 -P.sub.2 W.sub.17 MoO.sub.62 !.nH.sub.2 O
  • KHP.sub.2 V.sub.3 W.sub.15 O.sub.62.34H.sub.2 O
  • K.sub.6 �P.sub.2 W.sub.12 Nb.sub.6 O.sub.62 !.24H.sub.2 O
  • Na.sub.6 �V.sub.10 O.sub.28 !.18H.sub.2 O
  • (Guanidinium).sub.8 H�PV.sub.14 O.sub.62 !.3H.sub.2 O
  • K.sub.8 H�PV.sub.14 O.sub.62 !
  • Na.sub.7 �MnV.sub.13 O.sub.38 !.18H.sub.2 O
  • K.sub.6 �BW.sub.11 O.sub.39 Ga(OH.sub.2)!.13H.sub.2 O
  • K.sub.7 H�Nb.sub.6 O.sub.19 !.13H.sub.2 O
  • K.sub.7 H�Nb.sub.6 O.sub.19 !.13H.sub.2 O
  • �MeN/Na/K!.sub.4 �Nb.sub.2 W.sub.4 O.sub.19 !
  • �Me.sub.4 N!.sub.9 �P.sub.2 W.sub.15 Nb.sub.3 P.sub.62 !
  • �Me.sub.4 N!.sub.15 �HP.sub.4 W.sub.30 Nb.sub.6 O.sub.123 !.16H.sub.2 O
  • �Me.sub.4 N!.sub.15 �HP.sub.4 W.sub.30 Nb.sub.6 O.sub.123 !.16H.sub.2 O
  • �Na/K!.sub.6 Nb.sub.4 W.sub.2 O.sub.19 !
  • �Me.sub.4 N/Na/K!.sub.5 �Nb.sub.3 W.sub.3 O.sub.19 !.6H.sub.2 O
  • �Me.sub.4 N/Na/K!.sub.5 �Nb.sub.3 W.sub.3 O.sub.19 !.6H.sub.2 O
  • �Me.sub.5 CpRh).sub.4 V.sub.6 O.sub.19 !
  • K.sub.5 �CpTiSiW.sub.11 O.sub.39.12H.sub.2 O
  • b.sub.2 -K.sub.8 �SiW.sub.11 O.sub.39 !.14H.sub.2 O
  • a-K.sub.8 SiW.sub.10 O.sub.36 !.12H.sub.2 O
  • Cs.sub.7 Na.sub.2 �PW.sub.10 O.sub.37 !.8H.sub.2 O
  • Cs.sub.6 �P.sub.2 W.sub.5 O.sub.23 !.7(1/2)H.sub.2 O
  • g-Cs.sub.7 �PW.sub.10 O.sub.36 !.7H.sub.2 O
  • K.sub.5 �SiNbW.sub.11 O.sub.40 !.7H.sub.2 O
  • K.sub.4 �PNbW.sub.11 O.sub.40 !.12H.sub.2 O
  • Na.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.13H.sub.2 O
  • Na.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.20H.sub.2 O
  • K.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.7H.sub.2 O
  • K.sub.4 �V.sub.2 W.sub.4 O.sub.19 !.3.5H.sub.2 O
  • Na.sub.5 �V.sub.3 W.sub.3 O.sub.19 !.12H.sub.2 O
  • K.sub.6 �PV.sub.3 W.sub.9 O.sub.40 !.14H.sub.2 O
  • Na.sub.9 �A-b-GeW.sub.9 O.sub.34 !.8H.sub.2 O
  • Na.sub.10 �A-a-GeW.sub.9 O.sub.34 !.9H.sub.2 O
  • K.sub.7 �BY.sub.2 W.sub.10 O.sub.40 !.6H.sub.2 O
  • Na.sub.5 �CH.sub.3 Sn(Nb.sub.6 O.sub.19)!.10H.sub.2 O
  • Na.sub.5 �CH.sub.3 Sn(Nb.sub.6 O.sub.19)!.10H.sub.2 O
  • Na.sub.8 �Pt(P(m-SO.sub.3 Ph).sub.3).sub.3 Cl!.3H.sub.2 O
  • Na.sub.3 �P(m-SO.sub.3 Ph).sub.3 !.H.sub.2 O
  • (Me.sub.3 NH).sub.10 (H) �Si.sub.2 (ZrOH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 O
  • (Me.sub.3 NH).sub.10 (H) �Si.sub.2 (ZrOH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 O
  • K.sub.7 �A-a-GeNb.sub.3 W.sub.9 O.sub.40 !.18H.sub.2 O
  • K.sub.7 �A-b-SiNb.sub.3 W.sub.9 O.sub.40 !.20H.sub.2 O
  • (Me.sub.3 NH).sub.9 �A-a-HSi.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !
  • (Me.sub.3 NH).sub.9 �A-a-HGe.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !
  • (Me3NH).sub.9 �A-a-HGe.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !
  • K.sub.7 (H)�A-a-Ge.sub.2 Nb.sub.6 W.sub.18 O.sub.77 !.18H.sub.2 O
  • K.sub.8 �A-b-Si.sub.2 Nb.sub.6 W.sub.18 O.sub.77 ! and
  • (Me.sub.3 NH).sub.8 �A-b-Si.sub.2 Nb.sub.6 W.sub.18 O.sub.77 !.
  • 2. The method of claim 1, wherein said respiratory viral infection is influenza A.
  • 3. The method of claim 1, wherein said respiratory viral infection is influenza B.
  • 4. The method of claim 1, wherein said respiratory viral infection is RSV.
  • 5. The method of claim 1, wherein said polyoxometalate is selected from the group consisting of Na.sub.12 P.sub.2 W.sub.15 O.sub.56.18H.sub.2 O, Na.sub.16 Mn.sub.4 (H,O).sub.2 (P.sub.2 W.sub.15 O.sub.56).nH.sub.2 O, K.sub.10 Mn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O, K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O, (Me.sub.3 NH).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.NH.sub.2 O, (Me.sub.3 NH).sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O, (Me.sub.3 NH).sub.5 (NbO.sub.2)SiW.sub.11 O.sub.39, and K.sub.12 Nb.sub.6 P.sub.2 W.sub.12 O.sub.62.
  • 6. The method of claim 5, wherein said respiratory viral infection is influenza A.
  • 7. The method of claim 5, wherein said respiratory viral infection is influenza B.
  • 8. The method of claim 5, wherein said respiratory viral infection is RSV.
  • 9. The method of claim 1, wherein said polyoxometalate is K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O.
  • 10. The method of claim 9, wherein said respiratory viral infection is influenza A.
  • 11. The method of claim 9, wherein said respiratory viral infection is influenza B.
  • 12. The method of claim 9, wherein said respiratory viral infection is RSV.
  • 13. The method of claim 1, wherein said polyoxometalate is administered in the form of an aerosol.
  • 14. The method of claim 13, wherein said respiratory viral infection is influenza A.
  • 15. The method of claim 13, wherein said respiratory viral infection is influenza B.
  • 16. The method of claim 13, wherein said respiratory viral infection is RSV.
  • 17. The method of claim 1, wherein said polyoxometalate is (Me.sub.3 NH).sub.10 (H)�Si.sub.2 (ZrOH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 O.
  • 18. A pharmaceutical composition, comprising an effective amount of a polyoxometalate selected from the group consisting of
  • �(NMP).sub.2 H!.sub.3 PW.sub.12 O.sub.40
  • �(DMA).sub.2 H!.sub.3 PMo.sub.12 O.sub.40
  • (NH.sub.4).sub.17 Na�NaSb.sub.9 W.sub.21 O.sub.86 !
  • a- and b-H.sub.5 BW.sub.12 O.sub.40
  • a- and b-H.sub.6 ZnW.sub.12 O.sub.40
  • a- and b-H.sub.6 P.sub.2 W.sub.18 O.sub.62
  • .alpha.-(NH.sub.4).sub.6 P.sub.2 W.sub.18 O.sub.62
  • K.sub.10 Cu.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H.sub.2 O
  • K.sub.10 Co.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H.sub.2 O
  • Na.sub.7 PW.sub.11 O.sub.39
  • Na.sub.7 PW.sub.11 O.sub.39.20H.sub.2 O+2C.sub.6 H.sub.5 P(O)(OH).sub.2
  • (n-Bu.sub.4 N).sub.4 H.sub.3 PW.sub.11 O.sub.39
  • b-Na.sub.8 HPW.sub.9 O.sub.34
  • (n-Bu.sub.4 N).sub.3 PMoW.sub.11 O.sub.39
  • a-�(nBu).sub.4 N!.sub.4 Mo.sub.8 O.sub.26
  • (n-Bu.sub.4 N).sub.2 W.sub.6 O.sub.19
  • (n-Bu.sub.4 N).sub.2 Mo.sub.6 O.sub.19
  • a-(NH.sub.4).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • a-(NH.sub.4).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • a-K.sub.5 BW.sub.12 O.sub.40
  • K.sub.4 W.sub.4 O.sub.10 (O.sub.2)6
  • b-Na.sub.9 HSiW.sub.9 O.sub.34
  • Na.sub.6 H.sub.2 W.sub.12 O.sub.40
  • (NH.sub.4).sub.14 �NaP.sub.5 W.sub.30 O.sub.110 !
  • a-(NH.sub.4).sub.5 BW.sub.12 O.sub.40
  • a-Na.sub.5 BW.sub.12 O.sub.40
  • (NH.sub.4).sub.4 W.sub.10 O.sub.32
  • (Me.sub.4 N).sub.4 W.sub.10 O.sub.32
  • (HISH.sup.+).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • (LYSH.sup.+).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • (ARGH.sup.+).sub.n H.sub.(5-n) BW.sub.12 O.sub.40
  • (HISH.sub.+).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • (LYSH.sup.+).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • (ARGH.sup.+).sub.n H.sub.(4-n) SiW.sub.12 O.sub.40
  • a-K.sub.8 SiW.sub.11 O.sub.39
  • a-K.sub.8 SiW.sub.11 O.sub.39
  • K.sub.10 (H.sub.2 W.sub.12 O.sub.42)
  • K.sub.12 Ni.sub.3 (II)(PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • (NH.sub.4).sub.10 Co.sub.4 (II)(PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 Pd.sub.3 (II)(PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • Na.sub.12 P.sub.2 W.sub.15 O.sub.56.18H.sub.2 O
  • Na.sub.16 Cu.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Zn.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Co.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Ni.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56).sub.2.nH.sub.2 O
  • Na.sub.16 Mn.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 O.sub.56) .nH.sub.2 O
  • Na.sub.16 Fe.sub.4 (H.sub.2 O).sub.2 (P.sub.2 W.sub.15 l.sub.56).sub.2.nH.sub.2 O
  • K.sub.10 Zn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.20H.sub.2 O
  • K.sub.10 Ni.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.10 Mn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 Cu.sub.3 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 (Co H.sub.2 O).sub.3 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O
  • K.sub.12 Zn.sub.3 (PW.sub.9 O.sub.34).sub.2.15H.sub.2 O
  • K.sub.12 Mn.sub.3 (PW.sub.9 O.sub.34).sub.2.15H.sub.2 O
  • K.sub.12 Fe.sub.3 (PW.sub.9 O.sub.34).sub.2.25H.sub.2 O
  • (ARGH.sup.+).sub.10 (NH.sub.4).sub.7 Na�NaSb.sub.9 W.sub.21 O.sub.86 !
  • (ARGH.sub.+).sub.5 HW.sub.11 O.sub.39.17H.sub.2 O
  • K.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • �(CH.sub.3).sub.4 N!.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • Cs.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • �HISH+!.sub.7 Ti.sub.2 W.sub.10 O.sub.40
  • (LYSH+).sub.n Na.sub.7-n PTi.sub.2 W.sub.10 O.sub.40
  • (ARGH+).sub.n Na.sub.7-n PTi.sub.2 W.sub.10 O.sub.40
  • Cs.sub.4 �SiW.sub.11 O.sub.39.O(SiCH.sub.2 CH.sub.2 C(O)OCH.sub.3).sub.2 !.sub.4 -
  • �TBA!.sub.3 H.sub.3 V.sub.10 O.sub.28
  • K.sub.7 HNb.sub.6 O.sub.19.13H.sub.2 O
  • K.sub.8 Ta.sub.6 O.sub.19.17H.sub.2 O
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 -O(SiCH.sub.2 CH.sub.2 C(O)OCH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 CN)
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 PW.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl)
  • �(CH.sub.3).sub.4 N.sup.+ !.sup.4 PW.sub.11 O.sub.39 -(SiCH=CH.sub.2)
  • Cs.sub.4 �SWi.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 CN).sub.2 !
  • Cs.sub.4 �SiW.sub.11 O.sub.39 -(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl).sub.2 !
  • Cs.sub.4 �SiW.sub.11 O.sub.39 -(SiCH=CH.sub.2).sub.2 !
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 -O (SiCH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.2 CH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 -O(SiCH.sub.2 CH.sub.2 CH.sub.2 Cl).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 -O(SiCH.sub.2 CH.sub.2 CH.sub.2 CN).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 -O(SiCH=CH.sub.2).sub.2
  • �(CH.sub.2).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 -O(SiC(CH.sub.3).sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !SiW.sub.11 O.sub.39 -O(SiCH.sub.2 CH(CH.sub.3).sub.2).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.3 PW.sub.11 O.sub.39 -O(SiCH.sub.2 CH.sub.2 COOCH.sub.3).sub.2
  • K.sub.5 Mn(lI)PW.sub.11 O.sub.39 -nH.sub.2 O
  • K.sub.8 Mn(II)P.sub.2 W.sub.17 O.sub.61.nH.sub.2 O
  • K.sub.6 Mn(II)SiW.sub.11 O39.nH.sub.2 O
  • K.sub.5 PW.sub.11 O.sub.39 (SiMe.sub.2) .nH.sub.2 O
  • K.sub.3 PW.sub.11 O.sub.41 (PPh).sub.2.xH.sub.2 O
  • Na.sub.3 PW.sub.11 O.sub.41 (PPh).sub.2.xH.sub.2 O
  • K.sub.5 PTiW.sub.11 O.sub.40
  • Cs.sub.5 PTiW.sub.11 O.sub.39
  • K.sub.6 SiW.sub.11 O.sub.39 (SiMe.sub.2) .nH.sub.2 O
  • K.sub.3 PW.sub.11 O.sub.41 (PEt).sub.2.nH.sub.2 O
  • KSiW.sub.11 O.sub.39 �SiPh(t-BU)!.nH.sub.2 O
  • K.sub.6 SiW.sub.11 O.sub.39 (SiPh.sub.2) .nH.sub.2 O
  • K.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • Cs.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40 .nH.sub.2 O
  • Cs.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • (Me.sub.3 NH).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • (CN.sub.3 H.sub.6).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • (CN.sub.3 H.sub.6).sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • Rb.sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • Rb.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • K.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • K.sub.6 P.sub.2 Mo.sub.18 O.sub.62.nH.sub.2 O
  • (C.sub.5 H.sub.5 N).sub.7 HSi.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O
  • (C.sub.5 H.sub.5 N).sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O
  • (ARGH.sub.+).sub.8 SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 O
  • (LYSH.sup.+).sub.7 K SiW.sub.18 Nb.sub.6 O.sub.77.18H.sub.2 O
  • (HISH.sub.+).sub.6 K.sub.2 SiW.sub.18 Nb.sub.6 O.sub.77.18SH.sub.2 O
  • H.sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O (2 batches)
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub.2 CH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiCH.sub.3).sub.2
  • �(CH.sub.3).sub.4 N.sup.+ !.sub.4 SiW.sub.11 O.sub.39 --O(SiC.sub.16 H.sub.33).sub.2
  • Li.sub.7 HSi.sub.2 W.sub.18 Nb.sub.6 O.sub.77
  • Li.sub.9 P.sub.2 V.sub.3 Me.sub.3 W.sub.12 O.sub.62
  • Cs.sub.9 P.sub.2 V.sub.3 MeW.sub.l2 O.sub.62
  • Cs.sub.12 P.sub.2 V.sub.3 W.sub.12 O.sub.62
  • K.sub.4 H.sub.2 PV.sub.4 W.sub.8 O.sub.40
  • Na.sub.12 P.sub.4 W.sub.14 O.sub.58
  • Na.sub.14 H.sub.6 P.sub.6 W.sub.18 O.sub.79
  • a-K.sub.5 (NbO.sub.2) SiW.sub.11 O.sub.39
  • K.sub.5 (TaO.sub.2)SiW.sub.11 O.sub.39
  • (Me.sub.3 NH).sub.5 (NbO.sub.2)SiW.sub.11 O.sub.39
  • (Me.sub.3 NH).sub.5 NbSiW.sub.11 O.sub.40
  • (Me.sub.3 NH).sub.5 (TaO.sub.2) SiW.sub.11 O.sub.39
  • K.sub.4 (NbO.sub.2) PW.sub.11 O.sub.39
  • K.sub.7 (NbO.sub.2) P.sub.2 W.sub.12 O.sub.61
  • (Me.sub.3 NH).sub.7 (NbO.sub.2).sub.3 SiW.sub.9 O.sub.37
  • Cs.sub.7 (NbO.sub.2).sub.3 SiW.sub.9 O.sub.37
  • K.sub.6 (NbO.sub.2).sub.3 PW.sub.9 O.sub.37
  • Na.sub.10 (H.sub.2 W.sub.12 O.sub.42)
  • K.sub.4 NbPW.sub.11 O.sub.40
  • (Me.sub.3 NH).sub.4 NbPW.sub.11 O.sub.40
  • K.sub.5 NbSiW.sub.11 O.sub.40
  • K.sub.5 TaSiW.sub.11 O.sub.40
  • (Me.sub.3 NH).sub.5 TaSiW.sub.11 O.sub.40
  • K.sub.6 Nb.sub.3 PW.sub.9 O.sub.40
  • K.sub.7 NbP.sub.2 W.sub.17 O.sub.62
  • K.sub.7 (TiO.sub.2).sub.2 PW.sub.10 O.sub.38
  • K.sub.7 (TaO.sub.2).sub.3 SiW.sub.9 O.sub.37
  • K.sub.7 Ta.sub.3 SiW.sub.9 O.sub.40
  • K.sub.6 (TaO.sub.2).sub.3 PW.sub.9 O.sub.37
  • K.sub.6 Ta.sub.3 PW.sub.9 O.sub.40
  • K.sub.8 Co.sub.2 W.sub.11 O.sub.39
  • H.sub.2 (Me.sub.4 N).sub.4 (EtSi).sub.2 CoW.sub.11 O.sub.40
  • H.sub.2 (Me.sub.4 N).sub.4 (iso-C.sub.4 H.sub.9 Si).sub.2 CoW.sub.11 O.sub.40
  • K.sub.9 (NbO.sub.2).sub.3 P.sub.2 W.sub.15 O.sub.59
  • K.sub.9 Nb.sub.3 P.sub.2 W.sub.15 O.sub.62
  • K.sub.12 (NbO.sub.2).sub.6 P.sub.2 W.sub.12 O.sub.56
  • K.sub.12 Nb.sub.6 P.sub.2 W.sub.l2 O.sub.62
  • a.sub.2 -K.sub.10 P.sub.2 W.sub.17 O61
  • K.sub.6 Fe(III)Nb.sub.3 P.sub.2 W.sub.15 O.sub.62
  • K.sub.7 Zn(II)Nb.sub.3 P.sub.2 W.sub.15 O.sub.62
  • (NH.sub.4).sub.6 �a-P.sub.2 W.sub.18 O.sub.62 !.nH.sub.2 O
  • K.sub.12 �H.sub.2 P.sub.2 W.sub.12 O.sub.48 !.24H.sub.2 O
  • K.sub.12 �H.sub.2 P.sub.2 W.sub.12 O.sub.48 !.24H.sub.2 O
  • K.sub.2 Na.sub.1.5 H.sub.4.5 (PtMo.sub.6 O.sub.24.8H.sub.2 O
  • K.sub.6 �a.sub.2 -P.sub.2 W.sub.17 MoO.sub.62 !.nH.sub.2 O
  • KHP.sub.2 V.sub.3 W.sub.15 O.sub.62.34H.sub.2 O
  • K.sub.6 �P.sub.2 W.sub.12 Nb.sub.6 O.sub.62 !.24H.sub.2 O
  • Na.sub.6 �V.sub.10 O.sub.28 !.18H.sub.2 O
  • (Guanidinium).sub.8 H�PV.sub.14 O.sub.62 !.3H.sub.2 O
  • K.sub.8 H�PV.sub.14 O.sub.62 !
  • Na.sub.7 �MnV.sub.13 O.sub.38 !.18H.sub.2 O
  • K6�BW.sub.11 O.sub.39 Ga(OH.sub.2)!.13H.sub.2 O
  • K.sub.7 H�Nb.sub.6 O.sub.19 !.13H.sub.2 O
  • K.sub.7 H�Nb.sub.6 O.sub.19 !.13H.sub.2 O
  • �MeN/Na/K!.sub.4 �Nb.sub.2 W.sub.4 O.sub.19 !
  • �Me.sub.4 N!.sub.9 �P.sub.2 W.sub.15 Nb.sub.3 P.sub.62 !
  • �Me.sub.4 N!.sub.15 �HP.sub.4 W.sub.30 Nb.sub.6 O.sub.123 !.16H.sub.2 O
  • �Me.sub.4 N!.sub.15 �HP.sub.4 W.sub.30 Nb.sub.6 O.sub.123 !.16H.sub.2 O
  • �Na/K!.sub.6 Nb.sub.4 W.sub.2 O.sub.19 !
  • �Me.sub.4 N/Na/K!.sub.5 �Nb.sub.3 W.sub.3 O.sub.19 !.6H.sub.2 O
  • �Me.sub.4 N/Na/K!.sub.5 �Nb.sub.3 W.sub.3 O.sub.19 !.6H.sub.2 O
  • �Me.sub.5 CpRh).sub.4 V.sub.6 O.sub.19 !
  • K.sub.5 �CpTiSiW.sub.11 O.sub.39 !.12H.sub.2 O
  • b.sub.2 -K.sub.8 �SiW.sub.11 O.sub.39 !.14H.sub.2 O
  • a-K.sub.8 �SiW.sub.10 O.sub.36 !.12H.sub.2 O
  • Cs.sub.7 Na.sub.2 �PW.sub.10 O.sub.37 !.8H.sub.2 O
  • Cs.sub.6 �P.sub.2 W.sub.5 O.sub.23 !.7(1/2)H.sub.2 O
  • g-Cs.sub.7 �PW.sub.10 O.sub.36 !.7H.sub.2 O
  • K.sub.5 �SiNbW.sub.11 O.sub.40 !.7H.sub.2 O
  • K.sub.4 �PNbW.sub.11 O.sub.40 !.12H.sub.2 O
  • Na.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.13H.sub.2 O
  • Na.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.20H.sub.2 O
  • K.sub.6 �Nb.sub.4 W.sub.2 O.sub.19 !.7H.sub.2 O
  • K.sub.4 �V.sub.2 W.sub.4 O.sub.19 !.3.5H.sub.2 O
  • Na.sub.5 �(V.sub.3 W.sub.3 O.sub.19 !.12H.sub.2 O
  • K.sub.6 �PV.sub.3 W.sub.9 O.sub.40 !.14H.sub.2 O
  • Na.sub.9 �A-b GeW.sub.9 O.sub.34 !.8H.sub.2 O
  • Na.sub.10 �A-a-GeW.sub.9 O.sub.34 !.9H.sub.2 O
  • K.sub.7 �BY.sub.2 W.sub.10 O.sub.40 !.6H.sub.2 O
  • Na.sub.5 �CH.sub.3 Sn(Nb.sub.6 O.sub.19)!.10H.sub.2 O
  • Na.sub.5 �CH.sub.3 Sn(Nb.sub.6 O.sub.19)!.10H.sub.2 O
  • Na.sub.8 �Pt(P(m-SO.sub.3 Ph).sub.3).sub.3 Cl !.3H.sub.2 O
  • Na.sub.3 �P(m-SO.sub.3 Ph).sub.3 !.H.sub.2 O
  • (Me.sub.3 NH).sub.10 (H) �Si.sub.2 (ZroH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 O
  • (Me.sub.3 NH).sub.10 (H) �Si.sub.2 (ZrOH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 O
  • K.sub.7 �A-a-GeNb.sub.3 W.sub.9 O.sub.40 !.18H.sub.2 O
  • K.sub.7 �A-b-SiNb.sub.3 W.sub.9 O.sub.40 !.20H.sub.2 O
  • (Me.sub.3 NH).sub.9 �A-a-HSi.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !
  • (Me.sub.3 NH).sub.9 �A-a-HGe.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !
  • (Me.sub.3 NH).sub.9 �A-a-HGe.sub.2 Nb.sub.6 W.sub.18 O.sub.78 !
  • K.sub.7 (H) �A-a-Ge.sub.2 Nb.sub.6 W.sub.18 O.sub.77 !.18H.sub.2 O
  • K.sub.8 �A-b-Si.sub.2 Nb.sub.6 W.sub.18 O.sub.77 ! and
  • (Me.sub.3 NH).sub.8 �A-b-Si.sub.2 Nb.sub.6 W.sub.18 O.sub.77 !,
  • wherein said composition is in the form of an aerosol.
  • 19. The composition of claim 18, wherein said polyoxometalate is selected from the group consisting of Na.sub.12 P.sub.2 W.sub.15 O.sub.56.18H.sub.2 O, Na.sub.16 Mn.sub.4 (H,O).sub.2 (P.sub.2 W.sub.15 O.sub.56).nH.sub.2 O, K.sub.10 Mn.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O, K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O, (Me.sub.3 NH) .sub.7 SiW.sub.9 Nb.sub.3 O.sub.40.nH.sub.2 O, (Me.sub.3 NH).sub.8 Si.sub.2 W.sub.18 Nb.sub.6 O.sub.77.nH.sub.2 O, (Me.sub.3 NH).sub.5 (NbO.sub.2) SiW.sub.11 O.sub.39, and K.sub.12 Nb.sub.6 P.sub.2 W.sub.12 O.sub.62.
  • 20. The composition of claim 18, wherein said polyoxometalate is K.sub.10 Fe.sub.4 (H.sub.2 O).sub.2 (PW.sub.9 O.sub.34).sub.2.nH.sub.2 O.
  • 21. The composition of claim 18, wherein said polyoxometalate is (Me.sub.3 NH).sub.10 (H)�Si.sub.2 (ZrOH).sub.3 W.sub.18 O.sub.68 !.10H.sub.2 O.
CONTINUING DATA

This application is a continuation-in-part of application Ser. No. 08/312,561 filed Sep. 26, 1994 and now abandoned.

Government Interests

This invention was made with the assistance of U.S. Government funding under NIH Grant No. AI 32903. The U.S. Government may have some rights in this invention.

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Continuation in Parts (1)
Number Date Country
Parent 312561 Sep 1994