Synthesis and antibacterial activity of trivalent ultrashort Arg-Trp-based antimicrobialpeptides (AMPs)

Abstract

Multivalent display of identical ultrashort (only 2–3 amino acids long) antimicrobial peptides (AMPs) was used in order to create potential new antimicrobial agents. A series of small synthetic arginine and tryptophan containing peptides was synthesized and covalently bound to two different trivalent scaffold molecules using the copper(I)-catalyzed alkyne–azide cycloaddition (CuAAC) reaction. The effect of steric preorganization of AMPs on the antibacterial activity was studied using a 1,3,5-tris(azidomethyl)benzene and a 1,3,5-tris(azidomethyl)-2,4,6-triethylbenzene substituted scaffold. The comparison of these two scaffolds showed that preorganisation leads to at least twice as active compounds. We furthermore obtained a synergistic effect and could show that the presence of a certain number of amino acids in close proximity is more important than their relative spatial orientation.