HBS Constrained Antiparallel β-Sheets and Flat Toroid Turns; Homoserine, Thioamide and 1,3-Thiazine Containing Peptidomimetics: Design, Synthesis, Conformational Analyses and applications

Abstract

In chemical biology, short peptidomimetic biological active models have been widely used for anti-microbial activity, drug development, catalysis, and amyloidogenesis. In this thesis, I have synthesized several unnaturally constrained peptidomimetics, studied their conformations using spectrometric methods including NMR, FT-IR and CD and used them in chemical applications: In the H-bond surrogate (HBS) constrained convex anti-parallel β-sheet peptidomimetics two propyl linkers (N-CH2-CH2-CH2-N) HBS have been used to stabilize two shortest possible tripeptide strands into convex anti-parallel sheet conformations. The stereochemical control elements for their structure are elucidated. Their remarkably high thermal stabilities render them applicable in supramolecular chemistry and chemical biology. In another part, to mimic the functional principle of enzyme active sites in the small molecules, we have designed and synthesized flat rigid toroid cyclic peptides constrained by novel HBS analogs. Their residue side chains are oriented uniformly on one face of the cyclic surface, which is desirable for catalysis. The burial of these ionic groups in the desolvated environment of self-aggregated oligomers leads to Born-effect, where the pKas of the buried carboxylates get raised by 2-3 pH units compared to random coil values. In another application, small peptidomimetics containing the N-acyl-homoserine lactone (AHL) have been used to determine the structure-activity relationship in AHLs towards bacterial quorum sensing. In a related strategy, these thioamide homoserine lactone has been used as synthons for incorporating the 1,3-thiazine in the middle of the peptide chain and for the site-selective chemical cleavage, through competing 6-exo-tet and 5-exo-tet cyclization pathways respectively. These thioamide homoserine derivatives and 1,3-thiazine-containing peptides have been tested as potential modulators of amyloidogenesis with promising success.