The peptidomimetic approach for the design of viral protease inhibitors

The transformation of peptides into drug leads is an established approach in medicinal chemistry and drug discovery. Peptidomimetics are designed to mimic the bioactivity of peptides while addressing their limitations, such as poor metabolic stability and low bioavailability, thus resulting in improved receptor affinity and selectivity. Over last decades, a range of synthetic strategies has emerged to improve the pharmacological properties of these molecules through local and global conformational restrictions and introducing secondary structure mimetics. Herein the essential tools and methodologies in peptidomimetic design are reported with highlights to their therapeutic relevance, particularly in antiviral drug development. Peptidomimetics have shown notable success in targeting viral proteases as key enzymes involved in the life cycle of several pathogenic viruses. Case studies involving peptidomimetic inhibitors of HIV protease, HCV NS3/4A protease, SARS-CoV-2 main protease (3CLpro), and the NS2B-NS3 proteases of Zika and Dengue viruses are reported highlighting the efficacy of this approach, emphasizing the potential of peptidomimetic drugs as powerful tools in the treatment of infectious diseases.