Antimicrobial amino acid sequences derived from alpha-melanocyte-stimulating hormone

Abstract

The presence of the ancient anti-inflammatory peptide α-melanocyte stimulating hormone (α-MSH [1-13], SYSMEHFRWGKPV) in barrier organs such as gut and skin suggests a role in the nonspecific (innate) host defense system. α-MSH and other amino acid sequences derived from α-MSH were determined to have antimicrobial influences, including against two major and representative cutaneous and mucosal pathogens: Staphylococcus aureus and Candida albicans . C-MSH peptides had antimicrobial effects against S. aureus and significantly reversed the enhancing effect of urokinase on S. aureus colony formation. α-MSH and other amino acid sequences reduced C. albicans viability and germination. α-MSH peptides also enhanced C. albicans killing by human neutrophils. The antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence KPV, one or more peptides including the amino acid sequence MEHFRWG, or a biologically functional equivalent of any of the foregoing. The most effective of the peptides were those bearing the C-terminal amino acid sequence of α-MSH, i.e., α-MSH (1-13), (6-13), and (11-13). The α-MSH “core” sequence (4-10), important for melanotropic effects, was also effective but significantly less potent. Antimicrobial influences of α-MSH peptides could be mediated by their well-known capacity to increase cellular cAMP; this messenger was significantly augmented in peptide-treated yeast. α-MSH has potent anti-inflammatory effects and is expected to be useful for treatment of inflammation in human and veterinary disorders. Reduced killing of pathogens is a detrimental consequence of therapy with corticosteroids and nonsteroidal anti-inflammatory drugs during infection. Therefore, anti-inflammatory agents based on α-MSH peptides that do not reduce microbial killing, but rather enhance it, would be very useful. The antimicrobial effects of these α-MSH peptides occurred over a broad range of concentrations including the physiological (picomolar) range.

1 . (canceled)  
     
     
         2 . An antimicrobial agent selected from the group consisting of one or more peptides including the amino acid sequence KPV, one or more peptides including the amino acid sequence MEHFRWG, or a biologically functional equivalent of any of the foregoing.  
     
     
         3 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence KPV or a biologically functional equivalent of any of the foregoing.  
     
     
         4 . An antimicrobial agent according to  claim 3 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence KPV.  
     
     
         5 . An antimicrobial agent according to  claim 3 , wherein the entire amino acid sequence of the antimicrobial agent is KPV.  
     
     
         6 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence HFRWGKPV or a biologically functional equivalent of any of the foregoing.  
     
     
         7 . An antimicrobial agent according to  claim 6 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence HFRWGKPV.  
     
     
         8 . An antimicrobial agent according to  claim 7 , wherein the entire amino acid sequence of the antimicrobial agent is HFRWGKPV.  
     
     
         9 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence SYSMEHFRWGKPV or a biologically functional equivalent of any of the foregoing.  
     
     
         10 . An antimicrobial agent according to  claim 9 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence SYSMEHFRWGKPV.  
     
     
         11 . An antimicrobial agent according to  claim 10 , wherein the entire amino acid sequence of the antimicrobial agent is SYSMEHFRWGKPV.  
     
     
         12 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence MEHFRWG or a biologically functional equivalent of any of the foregoing.  
     
     
         13 . An antimicrobial agent according to  claim 12 , wherein the antimicrobial agent is selected from the group consisting of one or more peptides including the amino acid sequence MEHFRWG.  
     
     
         14 . An antimicrobial agent according to  claim 13 , wherein the entire amino acid sequence of the antimicrobial agent is MEHFRWG.  
     
     
         15 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent excludes naturally occurring a-MSH.  
     
     
         16 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent is further selected from the group consisting of one or more peptides having an amino acid chain length of up to thirteen.  
     
     
         17 . An antimicrobial agent according to  claim 16 , wherein the antimicrobial agent is further selected from the group consisting of one or more peptides having an amino acid chain length of up to eight.  
     
     
         18 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent is N-acetylated and C-amidated.  
     
     
         19 . An antimicrobial went according to  claim 2 , wherein the concentration of the antimicrobial agent is at least 10-12 molar.  
     
     
         20 . An antimicrobial agent according to  claim 19 , wherein the concentration of the antimicrobial agent is at least 10-6 molar.  
     
     
         21 . An antimicrobial agent according to  claim 2 , wherein the antimicrobial agent is effective against microbes including  Staphylococcus aureus  or  Candida albicans.