Rational Design of Macrocyclic Noncovalent Inhibitors of SARS-CoV-2 M pro from a DNA-Encoded Chemical Library Screening Hit That Demonstrate Potent Inhibition against Pan-Coronavirus Homologues and Nirmatrelvir-Resistant Variants

作者：Xu Wang, Xu Wang, Dimitar Gotchev, Kristi Fan, Marvin M. Vega, Nagraj Mani, Kayleigh R. McGovern-Gooch, Andrea Cuconati, Breanna Tercero, Xiaohe Wang, Xiaohe Wang, Philip A. Carpino, K. Maskos, Paolo A. Centrella, Andreas Schmitt, Franziska Preuß, Archna Prasad, Chia-yi Chen, Matthew A. Clark, John P. Guilinger, Shawn Johnstone, Konstanze von König, Anthony D. Keefe, Jenny Liu, Stéphane Turcotte, Ying Zhang, Débora L. Makino, Angela M. Lam, Andrew G. Cole, Michael J. Sofia · 发表于：Journal of Medicinal Chemistry · 年份：2024 · DOI：10.1021/acs.jmedchem.4c02009 · 被引用次数：7 · 研究领域：SARS-CoV-2 and COVID-19 Research、Computational Drug Discovery Methods、Bacteriophages and microbial interactions

The recent global COVID-19 pandemic has highlighted treatments for coronavirus infection as an unmet medical need. The main protease (M pro ) has been an important target for the development of SARS-CoV-2 direct-acting antivirals. Nirmatrelvir as a covalent M pro inhibitor was the first such approved therapy. Although M pro inhibitors of various chemical classes have been reported, they are generally less active against nirmatrelvir-resistant variants and have limited pan-coronavirus potential, presenting a significant human health risk upon future outbreaks. We here present a novel approach and utilized DNA-encoded chemical library screening to identify the noncovalent M pro inhibitor 5, which demonstrated a distinct binding mode to nirmatrelvir. A macrocyclization strategy designed to lock the active conformation resulted in lactone 12 with significantly improved antiviral activity. Further optimization led to the potent lactam 26, which demonstrated exceptional potency against nirmatrelvir-resistant variants as well as against a panel of viral main proteases from other coronaviruses.