Design, Synthesis and Conformational Analysis of Hybrid gamma-Peptide Foldamers Comprised of Proteinogenic Sidechains and Their Utilization in the Design of Novel Biomaterials

Abstract

Over the last two decades, backbone modified beta-peptide foldamers have been extensively investigated towards design of biologically active peptidomimetics. Comparatively, the foldamers containing gamma-amino acids with proteinogenic side-chains are less studied may be in part due to the difficulties in accessing enantiopure gamma-amino acids and possible chaos in folding of peptides due to the introduction of additional two torsional variables in each building block. In this regard, we sought to investigate the folding properties of hybrid peptides composed of gamma4-amino acids, their structural analogy with the protein secondary structures and their applications in biomaterials. Detailed investigations reveal that despite their increased backbone flexibility, gamma4-amino acids have showed a higher propensity towards helical organization even in the simple monomeric building block. The conformational analysis of various alpha, gamma4-hybrid peptides suggests that they adopt stable 12-helical conformations in solution and solid state. The structural analogy with alpha-peptide helices, beta-peptide 12-helix, helical wheel diagram, helical parameters and their hierarchical self-assembly of 12-helices into elongated peptide nanotubes have been investigated. In addition, conformationally biased unusual extended sheet type of structures from the homooligomers 4,4-dialkyl gamma-amino acids (Aic) and their spontaneous self-assembly into nanofibers and thermoreversible organogels in various organic solvents is studied. Besides this, we have also investigated the gamma4-amino acid mutated alpha-coiled coils as mild hyperthermia triggers for controlled release of entrapped molecules from liposomes. Based on these investigations, this thesis is divided into four chapters.