Design of a novel tryptophan-rich membrane-active antimicrobial peptide from the membrane-proximal region of the HIV glycoprotein, gp41

Evan F Haney,David J Schibli,Hans J Vogel,Leonard T Nguyen

doi:10.3762/bjoc.8.130

Abstract

A number of physicochemical characteristics have been described which contribute to the biological activity of antimicrobial peptides. This information was used to design a novel antimicrobial peptide sequence by using an intrinsically inactive membrane-associated peptide derived from the HIV glycoprotein, gp41, as a starting scaffold. This peptide corresponds to the tryptophan-rich membrane-proximal region of gp41, which is known to interact at the interfacial region of the viral membrane and adopts a helical structure in the presence of lipids. Three synthetic peptides were designed to increase the net positive charge and amphipathicity of this 19-residue peptide. Ultimately, the peptide with the greatest degree of amphipathicity and largest positive charge proved to be the most potent antimicrobial, and this peptide could be further modified to improve the antimicrobial activity. However, the other two peptides were relatively ineffective antimicrobials and instead proved to be extremely hemolytic. This work demonstrates a novel approach for the design of unexplored antimicrobial peptide sequences but it also reveals that the biological and cytotoxic activities of these polypeptides depend on a number of interrelated factors.

Highlights

Antimicrobial peptides (AMPs) continue to attract significant attention as potential alternatives to conventional antibiotics
In the case of gp41w-FKA, the hemolytic concentration was substantially higher than the minimum inhibitory concentration (MIC) and minimum bactericidal concentration (MBC) values (Table 1)
AMPs are often considered as potential therapeutic agents because of their selectivity towards bacterial cells and the perceived difficulty associated with bacteria in developing resistance to these molecules [21]

Summary

Introduction

Antimicrobial peptides (AMPs) continue to attract significant attention as potential alternatives to conventional antibiotics. The addition of detergent micelles and large unilamellar vesicles (LUVs) to the peptide solutions caused substantial blue shifts of the maximum wavelength in the Trp emission spectra (Figure 2B).

Results

Conclusion