Anticryptococcal activity and mechanistic investigation of histidine-rich short peptides

We report synthesis of short sequences with modified amphiphilic histidine and cationic arginine residues in an effort to develop new classes of peptides. The incorporation of 2-cycloalkyl and 1-aryl groups on the imidazole ring of histidine regulated the amphiphilicity and potency of the peptides. Peptides 15h [L-His(2-cyclohexyl)-L-Arg-L-His(1-(4-tert-butylphenyl)-NHBn] and 19k [L-His(1-biphenyl)-L-Arg-L-His-NHBn] exhibited potent anticryptococcal activity with IC50s of 2.66 mu g/mL and 4.40 mu g/mL against Cryptococcus neoformans, respectively. Peptides 15h and 19k displayed fungicidal effects on grow-ing fungal cells and exhibit synergistic activity with amphotericin B. Treatment with peptides lead to permeabilization and nuclear fragmentation of pathogenic fungi as depicted in the Confocal microscopy. SEM and TEM analysis of peptides showed shrinkage, disruption and pore(s) formation on cell mem-branes attributing to their rapid killing.(c) 2022 Elsevier B.V. All rights reserved.

Automated summary

We synthesized short sequences of peptides with modified amphiphilic histidine and cationic arginine residues to develop new classes of peptides. The incorporation of 2-cycloalkyl and 1-aryl groups on the histidine's imidazole ring regulated the peptides' amphiphilicity and potency. Peptides 15h and 19k showed potent anticryptococcal activity and exhibited synergistic effects with amphotericin B, leading to permeabilization and nuclear fragmentation of pathogenic fungi.