Modified histidine containing amphipathic ultrashort antifungal peptide, His[2-p-(n-butyl)phenyl]-Trp-Arg-OMe exhibits potent anticryptococcal activity

In pursuit of ultrashort peptide-based antifungals, a new structural class, His(2-aryl)-Trp-Arg is reported. Structural changes were investigated on His-Trp-Arg scaffold to demonstrate the impact of charge and lipophilic character on the biological activity. The presence and size of the aryl moiety on imidazole of histidine modulated overall amphiphilic character, and biological activity. Peptides exhibited IC50 of 0.37-9.66 mg/mL against C. neoformans. Peptide 14f [His(2-p-(n-butyl)phenyl)-Trp-Arg-OMe] exhibited twofold potency (IC50 = 0.37 mg/mL, MIC = 0.63 mu g/mL) related to amphotericin B, without any cytotoxic effects up to 10 mg/mL. Peptide 14f act by nuclear fragmentation, membranes permeabilization, disruption and pore formations in the microbial cells as determined by the mechanistic studies employing Trp-quenching, CLSM, SEM, and HR-TEM. The amalgamation of short sequence, presence of appropriate aryl group on L-histidine, potent anticryptococcal activity, no cytotoxicity, and detailed mechanistic studies directed to the identification of 14f as a new antifungal structural lead. (C) 2021 Elsevier Masson SAS. All rights reserved.

Automated summary

A new structural class of ultrashort peptide-based antifungal, His(2-aryl)-Trp-Arg, was reported in this study. Structural changes on the His-Trp-Arg scaffold showed the impact of charge and lipophilic character on biological activity. Peptide 14f exhibited potent anticryptococcal activity and showed no cytotoxic effects, acting through nuclear fragmentation, membrane permeabilization, and pore formations in microbial cells.