A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors

A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors

Bioorganic & Medicinal Chemistry Letters

10.1016/j.bmcl.2021.128263

http://dx.doi.org/10.1016/j.bmcl.2021.128263

Subramanyam Vankadara, Yun Xuan Wong, Boping Liu, Yi Yang See, Li Hong Tan, Qian Wen Tan, Gang Wang, Ratna Karuna, Xue Guo, Shu Ting Tan, Jia Yi Fong, Joma Joy, C.S. Brian Chia

Biochemistry, Molecular Biology, Molecular Medicine, Organic Chemistry, Pharmaceutical Science, Clinical Biochemistry, drug discovery

14 July 2021

Vankadara, S., Wong, Y. X., Liu, B., See, Y. Y., Tan, L. H., Tan, Q. W., Wang, G., Karuna, R., Guo, X., Tan, S. T., Fong, J. Y., Joy, J., & Chia, C. S. B. (2021). A head-to-head comparison of the inhibitory activities of 15 peptidomimetic SARS-CoV-2 3CLpro inhibitors. Bioorganic & Medicinal Chemistry Letters, 48, 128263. https://doi.org/10.1016/j.bmcl.2021.128263

The COVID-19 pandemic caused by SARS-CoV-2 has created an unprecedented global health emergency. As of July 2021, only three antiviral therapies have been approved by the FDA for treating infected patients, highlighting the urgent need for more antiviral drugs. The SARS-CoV-2 3CL protease (3CLpro) is deemed an attractive drug target due to its essential role in viral polyprotein processing and pathogenesis. Indeed, a number of peptidomimetic 3CLpro inhibitors armed with electrophilic warheads have been reported by various research groups that can potentially be developed for treating COVID-19. However, it is currently impossible to compare their relative potencies due to the different assays employed. To solve this, we conducted a head-to-head comparison of fifteen reported peptidomimetic inhibitors in a standard FRET-based SARS-CoV-2 3CLpro inhibition assay to compare and identify potent inhibitors for development. Inhibitor design and the suitability of various warheads are also discussed.

Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0)

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

https://oar.a-star.edu.sg/communities-collections/articles/16520

0960-894X

Experimental Drug Development Centre