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.

Description

TECHNICAL FIELD [0001] The present invention relates to new pharmaceutical compositions useful as antimicrobial agents, including, for example, for use in reducing the viability of microbes, reducing the germination of yeasts, killing microbes without reducing the killing of microbes by human neutrophils, for treating inflammation in which there is microbial infection without reducing microbial killing, and for increasing the accumulation of cAMP in microbes. More particularly, this invention relates to antimicrobial agents including amino acid sequences derived from alpha-melanocyte-stimulating hormone (α-MSH) and biologically functional equivalents thereof. BACKGROUND OF THE INVENTION [0002] Mucosal secretions, phagocytes, and other components of the nonspecific (innate) host defense system initiate the response to microbial penetration before time-consuming adaptive immunity starts. Survival of plants and invertebrates, which lack adaptive immunity, illustrates effectiveness of h...

AI Technical Summary

Benefits of technology

[0010] According to the invention, it has been determined that α-MSH and certain other amino acid sequences derived from α-MSH have significant antimicrobial uses, including for example, for use in reducing the viability of microbes, reducing the germination of yeasts, killing microbes without reducing the killing of microbes by human neutrophils, for treating inflammation in which there is microbial infection without reducing microbial killing, and increasing the accumulation of cAMP in microbes.

[0016] With these aspects of the invention, it is believed that the shorter amino acid sequences tend to be more effective. Preferably, 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. Still more preferably, 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. Based on the experimental results obtained thus far, the tripeptide KPV is the most effective.

[0018] It is fully expected that these peptides, which have extremely low toxicity, will be effective in animal and human subjects without adverse effect.

Problems solved by technology

The search for antimicrobial peptides, however, has been painfully difficult and slow.

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