Bicyclic temporin L peptide inhibitors targeting the SARS-CoV-2 main protease: design, synthesis,

Bicyclic peptides have emerged as promising inhibitors due to their high binding affinity and selectivity for target receptors. While peptide inhibitors are highly target-specific and exhibit strong protein-binding capabilities, their potential is often limited by challenges such as proteolytic instability and flexible secondary structures, which can reduce their efficacy and bioavailability. This study focuses on designing and synthesizing bicyclic peptides and their molecular dynamics insights using scaffolds like 1,3,5-tris(bromomethyl)benzene (TBMB) and 1,3,5-triacryloylhexahydro-1,3,5-triazine (TATA) to enhance their stability and efficacy. The inhibitory activity of these peptides was assessed by targeting the main protease (Mpro), a key enzyme in viral replication of SARS-CoV-2. Mass spectrometry confirmed the purity of these peptides, and their inhibitory activity was evaluated using fluorescence resonance energy transfer (FRET) and selected ion monitoring (SIM)-based LC-MS assays. Computational modeling and molecular dynamics (MD) simulations revealed the structural basis of peptide-Mpro interactions, highlighting improved conformational stability and binding mechanisms. Bicyclic peptides demonstrated superior inhibition compared to linear analogs, with constraints significantly improving peptide stability and binding properties. Our findings highlight the potential of bicyclic peptides as a robust platform for developing next-generation therapeutics with enhanced pharmacokinetic and pharmacodynamic profiles.