Antimicrobial peptides and methods of use

Patent metadata

Field	Value
Publication number	US-9346865-B2
Application number	US-201213588990-A
Country	US
Kind code	B2
Filing date	Aug 17, 2012
Priority date	Dec 15, 2004
Publication date	May 24, 2016
Grant date	May 24, 2016

Abstract

Disclosed herein are novel antimicrobial peptides with useful, improved, or superior properties such as antimicrobial activity, specificity, resistance to degradation desirable levels of hemolytic activity, and therapeutic index against a broad range of microorganisms including gram-negative and gram-positive bacteria and other organisms having a cellular or structural component of a lipid bilayer membrane. Also provided are methods of making and using such peptides to control microbial growth and in pharmaceutical compositions for treatment or prevention of infections caused by such microorganisms. Certain peptides result from structure-based rational design relating to antimicrobial peptide V681, with single D-/L-amino acid substitutions or charged residue substitutions in or near the center of the peptide on the nonpolar or polar face. Some peptides contain one or more (or all) amino acids in the D configuration. Compositions disclosed herein have useful clinical potential as antibiotics including broad spectrum antibiotics.

First claim

What is claimed is:

1. A method of increasing antimicrobial activity or decreasing hemolytic activity of an antimicrobial peptide comprising
producing a modified antimicrobial peptide by replacing at least one hydrophobic amino acid residue in a hydrophobic face of the antimicrobial peptide of SEQ ID NO:1 with at least one hydrophilic amino acid residue,
wherein the modified antimicrobial peptide produced is helical in a hydrophobic environment, and disordered in aqueous media.

2. The method of claim 1 , wherein the at least one hydrophilic amino acid residue is an amino acid residue having a negatively-charged side chain.

3. The method of claim 1 , wherein the at least one hydrophilic amino acid residue is an amino acid residue having a positively-charged side chain.

4. The method of claim 3 , wherein the at least one hydrophilic amino acid residue is a lysine amino acid residue.

5. The method of claim 1 , wherein the at least one hydrophilic amino acid residue is selected from the group consisting of D-lysine and D-alanine, and wherein all other amino acids residues in the modified antimicrobial peptide are in the L-enantiomeric form.

6. The method of claim 1 , wherein the modified antimicrobial peptide produced is selected from the group consisting of SEQ ID NO:24 and SEQ ID NO:25.

7. The method of claim 1 , wherein the modified antimicrobial peptide produced is selected from the group consisting of SEQ ID NO:6 and SEQ ID NO:9.

8. The method of claim 1 , wherein the modified antimicrobial peptide produced is selected from the group consisting of SEQ ID NO:10 and SEQ ID NO:11.

9. The method of claim 1 , wherein the producing step further comprises truncating one residue from an end of the antimicrobial peptide of SEQ ID NO:1.

10. The method of claim 1 , wherein the producing step further comprises truncating two residues from an end of the antimicrobial peptide of SEQ ID NO:1.

Assignees

• Hodges Robert S
• Chen Yuxin
• Univ Colorado Regents

Inventors

• Hodges Robert S
• Chen Yuxin

Classifications

• A61P31/12

  Antivirals · CPC title

• C07K14/4723 Primary

  Cationic antimicrobial peptides, e.g. defensins · CPC title

• A61P31/10

  Antimycotics · CPC title

• A61K38/00

  Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00) · CPC title

• A61P33/02

  Antiprotozoals, e.g. for leishmaniasis, trichomoniasis, toxoplasmosis · CPC title