Exploring the structural properties of alpha gamma hybrid peptide foldamers to design antimicrobials abeta42 oligomers aggregation inhibitors and nanotubes

Abstract

The structure and functions of proteins have inspired the design of new foldamers from organic templates and unnatural amino acid building blocks. In comparison to the foldamers derived from homogenous sequences of beta- and gamma-amino acid building blocks, heterogeneous sequences composed of alpha-, beta- and gamma-amino acids offered a variety of H-bonded protein secondary structure mimetics. Among the mixed peptide sequences, alpha, gamma- and alpha, alpha, gamma-hybrid peptides have been shown to adopt stable 12- and 10/12-helical conformations. We have explored the combination of alpha- and gamma-amino acid to design different types of protein secondary structure mimetics. The present work is mainly focusing on the design of alpha, gamma-hybrid peptides as Aand#61538;42 aggregation inhibitors, proteolytically stable peptide antibiotics, novel beta-double helix, and hybrid peptide nanotubes to measure protein-small molecule interactions. The designed amphiphilic cationic alpha, alpha, gamma-helical peptides displayed potent broad-spectrum antimicrobial activity (AMA) across the panel of Gram-positive, and Gram-negative bacteria including MRSA and VRSA. The results of Time Kill Analysis, Post Antibiotic Effect, Skin Infection Model, and other biophysical assays suggested that these alpha, alpha, gamma-helical peptides efficiently control the growth of the bacteria through instant membrane depolarization. In addition, we have also designed cationic amphiphilic peptides and alpha, alpha, gamma -hybrid peptides as Aand#61538;42 aggregation inhibitors. Among various Abeta-oligomers, Abeta1-42 (Abeta42) is known to be highly aggregation-prone and also toxic. The designed peptides not only inhibit the soluble Abeta42 into aggregated fibrils but also disintegrate matured fibrils of Abeta42 into smaller assemblies. The biophysical analysis comprising the Thioflavin T assay, CD, 2D-NMR HSQC, DLS, and ELISA assays revealed that upon interaction the peptide induces a conformational change in the Abeta42. Further, the cell assay