Design of 16-residue peptides possessing antimicrobial and hemolytic activities or only antimicrobial activity from an inactive peptide

Abstract

We have explored the possibility of generating peptides having antimicrobial and hemolytic activities or only antimicrobial activity, from a 16-residue peptide, GFFALIPKIISSPLFK, corresponding to the N-terminal region of the toxin pardaxin. This peptide does not exibit these activities, although it can permeabilize model membranes. Peptides were synthesized wherein either A4 or P7 were substituted by K and S11 replaced by K, Peptides in which P7 and S11 were replaced with K, (AK) and A4 and S11 replaced with K and A instead of P at position 7, (KA) showed potent antimicrobial and hemolytic activities. However, the peptide where S11 and A4 were replaced with K, (KP) showed pronounced antimicrobial activity with very weak hemolytic activity. Circular dichroism studies indicated that peptides AK and KA had a strong propensity to occur in a helical conformation, whereas KP did not. Peptides AK and KA were very effective in permeabilizing model membranes, whereas KP was relatively ineffective. Our studies thus suggest the requirements for a peptide to have only antimicrobial activity and also that selectivity in activity can be rationalized on the basis of biophysical principles. Thus, by judicious positioning of amino acids, especially positively charged ones, it should be possible to generate biologically active peptides without taking recourse to a combinatorial approach.