Design, Synthesis, and Bioactivity of Thioamidated Macrocyclic Peptides

Abstract

The work presented in this thesis describes the comprehensive study related to thioamidated macrocyclic peptides. We study the underexplored class of peptide bond isostere; thioamides in the context of small macrocyclic peptides The thesis is divided into six chapters. First chapter introduces the literature available for macrocyclic peptides along with the various peptide backbone modifications, and challenges associated with the study of thioamidated peptides. In the second chapter, we have focussed on the optimization of synthetic protocol for the incorporation of a thioamidated residue in site-selective manner in linear and cyclic peptides. Subsequently, in chapter 3 efforts have been put to understand the conformational impact of thioamide incorporation on the backbone of macrocyclic peptides. Understanding the detailed role of bioactivity in structurally characterised thioamidated peptides is the main focus of chapters 4 and 5. Detailed experimental and computational analysis lead us to propose thioamide as a bioisosteric modification that would greatly aid in the development of leads in peptide-based drug discovery efforts. Chapter 6 deals with the summary and conclusion of the work. The later part of thesis has Appendices, each appendix describes the materials and methods used in preceding chapters and characterization of various synthesised thioamidated amino acid precursors and peptides used in this study, via HRMS, HPLC and NMR.