A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir

ACS Medicinal Chemistry Letters

10.1021/acsmedchemlett.2c00260

http://dx.doi.org/10.1021/acsmedchemlett.2c00260

Subramanyam Vankadara, Monique Danielle Dawson, Jia Yi Fong, Qin Yao Oh, Qi An Ang, Boping Liu, Hong Yun Chang, Judice Koh, Xiaoying Koh, Qian Wen Tan, Joma Joy, Cheng San Brian Chia

Biochemistry, Organic Chemistry, drug discovery

19 July 2022

Vankadara, S., Dawson, M. D., Fong, J. Y., Oh, Q. Y., Ang, Q. A., Liu, B., Chang, H. Y., Koh, J., Koh, X., Tan, Q. W., Joy, J., & Chia, C. S. B. (2022). A Warhead Substitution Study on the Coronavirus Main Protease Inhibitor Nirmatrelvir. ACS Medicinal Chemistry Letters, 13(8), 1345–1350. https://doi.org/10.1021/acsmedchemlett.2c00260

The SARS-CoV-2 pandemic is currently causing an unprecedented global health emergency since its emergence in December 2019. In December 2021, the FDA granted emergency use authorization to nirmatrelvir, a SARS-CoV-2 main protease inhibitor, for treating infected patients. This peptidomimetic is designed with a nitrile warhead, which forms a covalent bond to the viral protease. Herein, we investigate nirmatrelvir analogs with different warheads and their inhibitory activities. In addition, antiviral activities against human alphacoronavirus 229E was also investigated along with a cell-based assay. We discovered that the hydroxymethylketone and ketobenzothiazole warheads were equipotent to the nitrile warhead, suggesting that these analogs can also be used for treating coronavirus infections.

Publisher Copyright

This research is supported by core funding from: Experimental Drug Development Centre
Grant Reference no. : NRF2021-IE-IECF-001

This document is the Accepted Manuscript version of a Published Work that appeared in final form in ACS Medicinal Chemistry Letters, copyright © American Chemical Society after peer review and technical editing by the publisher. To access the final edited and published work see doi.org/10.1021/acsmedchemlett.2c00260

https://oar.a-star.edu.sg/communities-collections/articles/19034

1948-5875

Experimental Drug Development Centre