Claims
- 1. A backbone-cyclized peptidomimetic of a fragment of bacterial/permeability increasing protein 23 (BPI23) having anti-fungal activity comprising the following BPI23 peptide sequence:(SEQ ID NO:1)Q-Lys-Trp-Leu-Ile-Gln-Leu-Phe-His-Lys-Lys-E 152 156 161wherein: Q represents H or an acyl group; E represents a hydroxyl group, a carboxyl protecting group or an amino group, or the carboxy terminal group CO—E, wherein the CO is part of an amino acid residue, can be reduced to CH2—OH or CHO and wherein up to four amino acid residues of the BPI23 peptide sequence, amino acid residues 153-160, are replaced with a building unit, a different amino acid residue or is absent and wherein the BPI23 peptide sequence has at least one building unit with at least one backbone nitrogen in the peptide sequence linked to a side chain of at least one other amino acid in the peptide sequence or to at least one other backbone nitrogen in the peptide sequence by a bridging group comprising a disulfide, amide, thioether, thioester, imine, ether, or alkene to form a backbone-cyclized peptidomimetic having anti-fungal activity.
- 2. The peptidomimetic of claim 1, wherein at least two building units are incorporated in the BPI23 peptide sequence.
- 3. The peptidomimetic of claim 1, wherein at least one pair of backbone nitrogens in the BPI23 peptide sequence are linked together.
- 4. The peptidomimetic of claim 1, wherein the bridging group has the formula:(i) —X—M—Y—W—Z—; or (ii) —X—M—Z—wherein: M and W are independently selected from the group consisting of disulfide, amide, thioether, thioester, imine, ether, and alkene; and X, Y and Z are each independently selected from the group consisting of alkylene, substituted alkylene, arylene, homo- or hetero-cycloalkylene and substituted cycloalkylene.
- 5. The peptidomimetic of claim 4 wherein —X—M—Y—W—Z— is: —(CH2)x—M—(CH2)y—W—(CH2)2— wherein M and W are as recited above; x and z each independently designates an integer of from 1 to 10, and y is zero or an integer of 1 to 8, with the proviso that if y is zero, W is absent.
- 6. The peptidomimetic of claim 1, wherein at least one backbone nitrogen is cyclized to a side-chain of an amino acid.
- 7. The peptidomimetic of claim 1, wherein the building unit is an Nα-ω-functionalized derivative of amino acids of formula (IV): wherein X is a spacer group selected from the group consisting of alkylene, substituted alkylene, arylene, cycloalkylene and substituted cycloalkylene; R′ is an amino acid side chain, optionally bound with a specific protecting group; and G is a functional group selected from the group consisting of amines, thiols, alcohols, carboxylic acids and esters, and alkyl halides, wherein the building unit is incorporated into BPI23 peptide sequence and cyclized via the functional group G with one of the side chains of the amino acids in said peptide sequence or with another ω-functionalized amino acid derivative.
- 8. A backbone-cyclized peptidomimetic of a fragment of bacterial/permeability increasing protein 23 comprising a peptide sequence having at least one building unit having an Nα-derivative of an amino acid, wherein at least one backbone nitrogen in the peptide sequence is linked to a side chain of at least one other amino acid in the peptide sequence or to at least one other backbone nitrogen in the peptide sequence by a bridging group comprising a disulfide, amide, thioether, thioester, imine, ether, or alkene to form a backbone-cyclized peptidomimetic, wherein the peptide sequence has the formula:Q-Lys-AA2-AA3-AA4-AA5-AA6-AA7-AA8-AA-9-Lys-E wherein: Q represents H or an acyl group; E represents a hydroxyl group, a carboxyl protecting group or an amino group, or the carboxy terminal group CO—E, wherein the CO is part of an amino acid residue, can be reduced to CH2—OH or CHO; AA2 is Trp, 2Nal, D2Nal, 1Nal, D1Nal, Gly-C*, or Gly-N*; AA3 is Leu, Gly-C* or Gly-N*; AA4 is absent, Ile, Gly Ala, Gly-C* or Gly-N*; AA5 is Gln, Gly-C* or Gly-N*; AA0 is Leu, Gly-C* or Gly-N*; AA7 is Phe, DPhe, Phg, pNO2Phe, pFPhe, Gly-C* or Gly-N*; AA8 is His, Gly-C* or Gly-N*; AA9 is Lys, Gly-C* or Gly-N*; and * is an integer from 1 to 3, wherein a bridging group extends from one of AA2, AA3, or AA5 to one of AA6, AA7, AA8, or AA9 to form a cyclic structure having anti-fungal activity.
- 9. The backbone-cyclized peptidomimetic of claim 8, wherein AA2 is Trp or Gly-C2; AA3 is Leu or Gly-C2; AA4 is Ile or Gly-C2; AA5 is Gln or Gly-C2; AA6 is Leu or Gly-N2; AA7 is Phe or Gly-N2; AA8 is His or Gly-N2; and AA9 is Lys or Gly-N2.
- 10. The backbone-cyclized peptidomimetic of claim 9, wherein AA2 is Gly-C2; AA3 is Leu; AA4 is Ile; and AA5 is Gln.
- 11. The backbone-cyclized peptidomimetic of claim 9, wherein AA2 is Gly-C2; AA3 is Leu; AA4 is Ile; and AA5 is Gln; AA6 is Leu; AA7 is Phe; AA8 is Gly-N2; and AA9 is Lys.
- 12. The backbone-cyclized peptidomimetic of claim 8, wherein AA1 is Lys; AA2 is Trp; AA3 is Leu; AA4 is Ile, Gly or Ala; AA5 is Gly-C2; AA6 is Leu; AA7 is Phe, DPhe, Phg, pNO2Phe, or pFPhe; AA8 is His; and AA9 is Gly-N2.
- 13. The backbone-cyclized peptidomimetic of claim 8, wherein AA1 is Lys; AA2 is 2Nal, D2Nal, 1Nal, or D1Nal; AA3 is Gly-C1, Gly-C2, Gly-N2 or Gly-N3; AA4 is Ile; AA5 is Gln; AA6 is Leu; AA7 is Phe; AA8 is Gly-C1, Gly-C2, Gly-N2 or Gly-N3; and AA9 is Lys, wherein if AA3 is Gly-C1 or Gly-C2, AA8 is Gly-N2 or Gly-N3, and if AA3 is Gly-N2 or Gly-N3, AA8 is Gly-C1 or Gly-C2.
- 14. The backbone-cyclized peptidomimetic of claim 13, wherein AA2 is 1Nal.
CROSS-REFERENCE TO RELATED APPLICATIONS
This application is a division of U.S. application Ser. No. 08/569,042, filed Dec. 7, 1995, now U.S. Pat. No. 6,117,974 the content of which is expressly incorporated herein by reference thereto.
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