Molecular craftsmanship: reforging peptide backbones for enhanced drug design

Abstract

This review analyzes peptide backbone modifications in drug design, examining fundamental principles and applications in pharmaceutical development. A systematic classification of modification approaches encompasses amide bond alterations, α-carbon modifications, backbone extensions and conformational constraints. The analysis evaluates synthetic methodologies, computational tools and biological outcomes, emphasizing clinical translation barriers. Critical examination of current design paradigms reveals systematic biases and unexpected effects while advancing theoretical frameworks incorporating multi-scale phenomena. The work addresses computational modeling limitations, regulatory requirements and production challenges, presenting evidence-based solutions. This integration of chemical, biological and computational perspectives provides a foundation for advancing peptide-based therapeutics.