Macrocycles and stapled-peptides in the fight against SARS-CoV-2: a review

The development of innovative therapeutic strategies for challenging biological targets has led to a resurgence of interest in macrocyclic and peptide-stapled compounds. The conformationally constrained architectures of these compounds enable high affinity, selectivity, and improved pharmacokinetic profiles compared with linear analogues. These properties position macrocycles and stapled-peptides as promising platforms for the development of next-generation therapeutics, including antiviral agents addressing emerging diseases such as COVID-19. In six years, the scientific community has provided several structure-activity relationship studies in which the anti-SARS-CoV-2 effects of macrocycles and stapled-peptides have been reported. The present review aims to discuss macrocycles and stapled-peptides with inhibitory properties against SARS-CoV-2 infection. A particular focus has been addressed to the design of cyclic entities, effect of ring size, presence of unnatural amino acids, stapling position, stereochemistry, role of linkers, pan-antiviral effects, metabolic stability assessment, and selectivity profile, among others. Comparisons with linear counterparts were discussed, wherever applicable, to elucidate the differences in terms of biological properties towards the target, antiviral effects in cell-based assays, molecular architecture, and proteolytic resistance. Overall, the development of macrocycles and stapled-peptides against SARS-CoV-2 was found to be a productive strategy for the identification of novel and effective antiviral agents. Furthermore, future challenges and perspectives have been discussed.