Abstract:
Recent advances in foldamers composed of non-natural β- and γ- amino acids suggested the greater structural diversity in hybrid peptides constituted with mixed αβ, αγ and βγ sequences compared to their homooligomers. The remarkable structural diversity in αβ-hybrid peptides has been exploited to design specific inhibitors for protein-protein interactions, antimicrobials and biomaterials. In comparison with αβ-hybrid peptides, αγ-hybrid peptides have not been extensively explored to design either biologically active molecules or biomaterials. In this context, we sought to investigate the folding behaviour of αγ-hybrid peptides composed of γ- and β-hydroxy γ-amino acids (statins) and their potential antimicrobial properties. Herein, we are reporting the design, synthesis, single crystal conformations of various novel α,α,γ-peptides incorporated with γ- and statins and their potential antimicrobial properties. The single crystal conformational analysis suggests that αγ-hybrid peptides adopt 10/12 helical conformations with or without stereochemically constrained amino acids. The helical structures of αγ-hybrid peptides are stabilized by i+4-i intramolecular H-bonds. Instructively, 10/12-helices showed similarities in the H-bonding pattern (residue to residue) and side-chain projection with 310-helix of α-peptides and β-peptide 12-helix. Further, our studies also infer that biologically active, naturally occurring β-hydroxy γ-amino acids can be accommodated into the helix without deviating overall helical fold. In addition to the conformational analysis, we have also designed and synthesized water soluble hybrid peptides incorporated with γ4-amino acids and investigated their potential anti-microbial properties. Results of these studies suggests that peptides incorporated with statin anti diastereoisomer shows better potency against various bacteria as compared to that of peptides incorporated with syn diastereoisomer and γ4-amino acids.
