Insights into the conformational stability & pharmacology of peptides through side chain and backbone modification

Abstract

The first part of the work presented in the thesis deals with CH-pi interaction, which is a lesser-known non-covalent interaction in proteins. We identified several CH-pi donor-acceptor pairs involving amino acids side chains and less polarized C-H bonds at a solvent-exposed site between the strands of a model beta-hairpin peptide. Therein, we observe a distance-dependent induction of CH-pi interaction within the aliphatic-aromatic amino acid pair. Our results also suggest an interplay of hydrophobicity and CH-pi interaction in dictating the stability of beta-hairpin. In the second part, we have attempted to establish thioamidation, which is a single atom ‘O’ to ‘S’ substitution, as a chemical strategy for amide bond desolvation. Thioamide substitution on a model and a bioactive cyclic peptide has led to an enhancement in membrane permeability and metabolic stability which are the two major deterrents of peptide bioavailability. We observed improved plasma exposure of the thioamidated peptides upon oral intake. Thioamidation could successfully improve the pharmacokinetic properties of the peptides and subsequently, their oral bioavailability. Additionally, thioamidated somatostatin agonists displayed prolonged inhibition of growth hormone release in vivo. Altogether, the work done in this thesis highlights the roles of both side chains and amide backbone in modulating conformations and other functional properties of peptides and proteins. Our strategies underscore how these local components can be fine-tuned to achieve the desired biophysical properties and activities to design next generation peptide-based therapeutics.