Design of improved synthetic antifungal peptides with targeted variations in charge, hydrophobicity and chirality based on a correlation study between biological activity and primary structure of plant defensin gamma-cores

摘要

Microbial resistance to available drugs is a growing health threat imposing the need for the development of new drugs. The scaffold of plant defensins, including their gamma-cores, are particularly good candidates for drug design. This work aimed to improve the antifungal activity of a previous design peptide, named A(36),(42),(44)gamma(32-46)VuDef (for short DD) against yeasts by altering its biochemical parameters. We explore the correlation of the biological activity and structure of plant defensins and compared their primary structures by superimposition with VuDef(1) and DD which indicated us the favorable position and the amino acid to be changed. Three new peptides with modifications in charge, hydrophobicity (RR and WR) and chirality (D-RR) were designed and tested against pathogenic yeasts. Inhibition was determined by absorbance. Viability of mammalian cells was determined by MTT. The three designed peptides had better inhibitory activity against the yeasts with better potency and spectrum of yeast species inhibition, with low toxicity to mammalian cells. WR, the most hydrophobic and cationic, exhibited better antifungal activity and lower toxicity. Our study provides experimental evidence that targeted changes in the primary structure of peptides based on plant defensins gamma-core primary structures prove to be a good tool for the synthesis of new compounds that may be useful as alternative antifungal drugs. The method described did not have the drawback of synthesis of several peptides, because alterations are guided. When compared to other methods, the design process described is efficient and viable to those with scarce resources.