ANTIMICROBIAL PEPTIDES WITH ALPHA-CORE HELICES
The present disclosure describes the identification of a consensus formula representing α-helical antimicrobial peptides (AHAPs) from broad classes of higher eukaryotes. Further provided are microbicidal peptides, compositions, methods, and uses, and computer systems and methods for identifying consensus formulae and for searching microbicidal peptides. In some embodiments, the peptide or fusion peptide includes one or more non-natural amino acid residues. Also provided is a composition comprising the α-helical antimicrobial peptide or the fusion peptide, and a pharmaceutically acceptable carrier. Also provided is a method of treating an infection in a patient in need thereof, comprising administering to the patient an effective amount of a composition comprising an α-helical antimicrobial peptide.
1 . An isolated peptide comprising an amino acid sequence selected from the group consisting of SEQ ID NO: 1-14, and an amino acid derived from anyone of SEQ ID NO: 1-14 with one amino acid substitution, wherein the peptide is not longer than 100 amino acid residues in length.
2 . The isolated peptide of claim 1 , wherein the peptide has antimicrobial activity.
3 . The isolated peptide of claim 1 , wherein the peptide comprises the amino acid sequence of anyone of SEQ ID NO: 1-14.
4 . The isolated peptide of claim 1 , wherein the peptide comprises the amino acid sequence of SEQ ID NO: 13 or 14.
5 . The isolated peptide of claim 1 , wherein the peptide is not longer than 75 amino acid residues in length.
6 . The isolated peptide of claim 1 , wherein the peptide is not longer than 60 amino acid residues in length.
7 . An isolated peptide comprising an amino acid sequence of SEQ ID NO:19-6860 or an amino acid derived from a sequence of SEQ ID NO:19-6860 with one amino acid substitution, wherein the peptide is not longer than 100 amino acid residues in length.
8 . A fusion peptide comprising a first fragment comprising the peptide of claim 7 , and a second fragment having antimicrobial activity, wherein the fusion peptide is not longer than 100 amino acid residues in length.
9 . The fusion peptide of claim 8 , wherein the second fragment comprises a gamma-core motif comprising two anti-parallel β-sheets interposed by a short turn region with a GXC or CXG sequence pattern integrated into one of the β-sheets.
10 . The fusion peptide of claim 9 , wherein the gamma-core motif comprises CPTAQLIATLKNGRKICLDLQ (SEQ ID NO: 15) or a first amino acid sequence having at least 85% sequence identity to SEQ ID NO: 15.
11 . The peptide of claim 1 , comprising one or more non-natural amino acid residues.
12 . A composition comprising the peptide of claim 1 , and a pharmaceutically acceptable carrier.
13 . The composition of claim 12 , further comprising an antimicrobial agent.
14 . The composition of claim 13 , wherein the antimicrobial agent is selected from the group consisting of imipenem, ceftazidime, colistin, chloroquine, artemisinin, vancomycin and daptomycin.
15 . A method of treating an infection in a patient in need thereof, comprising administering to the patient an effective amount of the composition of claim 12 .
16 . The method of claim 15 , wherein the infection is caused by a Gram-negative bacterium, a Gram-positive bacterium or a fungus.
17 . A computer-implemented method of identifying a peptide having antimicrobial activity, comprising:
identifying a consensus formula from aligned amino acid sequences known to have an antimicrobial activity;
tuning the consensus formula with a test search against a plurality of proteins with known antimicrobial activity; and
searching in a protein database, with one or more processors, for amino acid fragments matching the consensus formula, wherein the search takes as input one or more criteria selected from the group consisting of location of the fragment in a protein, size of the protein, organism of the protein, and signal peptide of the protein.
18 . The method of claim 17 , wherein the tuning comprising shortening the length of the consensus formula or changing substation options at one or more amino acid residues.
19 . (canceled)