Monday, April 1, 2024

Azapeptides with unique covalent warheads as SARS-CoV-2 main protease inhibitors

Kaustav Khatua, Yugendar R. Alugubelli , Kai S. Yang, Veerabhadra R. Vulupala, Lauren R. Blankenship , Demonta Coleman, Sandeep Atla , Sankar P. Chaki, Zhi Zachary Geng , Xinyu R. Ma , Jing Xiao , Peng-Hsun Chen , Chia-Chuan D. Cho, Shivangi Sharma, Erol C. Vatansever, Yuying Ma, Ge Yu, Benjamin W. Neuman, Shiqing Xu , Wenshe Ray Liu

Antiviral Research, 225, 2024, 105874

https://doi.org/10.1016/j.antiviral.2024.105874

The main protease (MPro) of SARS-CoV-2, the causative agent of COVID-19, is a pivotal nonstructural protein critical for viral replication and pathogenesis. Its protease function relies on three active site pockets for substrate recognition and a catalytic cysteine for enzymatic activity. To develop potential SARS-CoV-2 antivirals, we successfully synthesized a diverse range of azapeptide inhibitors with various covalent warheads to target MPro's catalytic cysteine. Our characterization identified potent MPro inhibitors, including MPI89 that features an aza-2,2-dichloroacetyl warhead with a remarkable EC50 value of 10 nM against SARS-CoV-2 infection in ACE2+ A549 cells and a selective index of 875. MPI89 is also remarkably selective and shows no potency against SARS-CoV-2 papain-like protease and several human proteases. Crystallography analyses demonstrated that these inhibitors covalently engaged the catalytic cysteine and used the aza-amide carbonyl oxygen to bind to the oxyanion hole. MPI89 stands as one of the most potent MPro inhibitors, suggesting the potential for further exploration of azapeptides and the aza-2,2-dichloroacetyl warhead for developing effective therapeutics against COVID-19.




Selective Covalent Inhibiting JNK3 by Small Molecules for Parkinson's Diseases

Liang Ouyang, Wen Shuai, Panpan Yang, Huan Xiao, Yumeng Zhu, Faqian Bu, Aoxue Wang, Qiu Sun, Guan Wang Angewandte Chemie   2024 e202411037 ...