A Quick Route to Multiple Highly Potent SARS-CoV-2 Main Protease Inhibitors**

Kai S. Yang, Xinyu R. Ma, Yuying Ma, Yugendar R. Alugubelli, Danielle A. Scott, Erol C. Vatansever, Aleksandra K. Drelich, Banumathi Sankaran, Zhi Z. Geng, Lauren R. Blankenship, Hannah E. Ward, Yan J. Sheng, Jason C. Hsu, Kaci C. Kratch, Baoyu Zhao, Hamed S. Hayatshahi, Jin Liu, Pingwei Li, Carol A. Fierke, Chien Te K. TsengShiqing Xu, Wenshe Ray Liu

Research output: Contribution to journalArticlepeer-review

75 Scopus citations


The COVID-19 pathogen, SARS-CoV-2, requires its main protease (SC2MPro) to digest two of its translated long polypeptides to form a number of mature proteins that are essential for viral replication and pathogenesis. Inhibition of this vital proteolytic process is effective in preventing the virus from replicating in infected cells and therefore provides a potential COVID-19 treatment option. Guided by previous medicinal chemistry studies about SARS-CoV-1 main protease (SC1MPro), we have designed and synthesized a series of SC2MPro inhibitors that contain β-(S-2-oxopyrrolidin-3-yl)-alaninal (Opal) for the formation of a reversible covalent bond with the SC2MPro active-site cysteine C145. All inhibitors display high potency with Ki values at or below 100 nM. The most potent compound, MPI3, has as a Ki value of 8.3 nM. Crystallographic analyses of SC2MPro bound to seven inhibitors indicated both formation of a covalent bond with C145 and structural rearrangement from the apoenzyme to accommodate the inhibitors. Virus inhibition assays revealed that several inhibitors have high potency in inhibiting the SARS-CoV-2-induced cytopathogenic effect in both Vero E6 and A549/ACE2 cells. Two inhibitors, MPI5 and MPI8, completely prevented the SARS-CoV-2-induced cytopathogenic effect in Vero E6 cells at 2.5–5 μM and A549/ACE2 cells at 0.16–0.31 μM. Their virus inhibition potency is much higher than that of some existing molecules that are under preclinical and clinical investigations for the treatment of COVID-19. Our study indicates that there is a large chemical space that needs to be explored for the development of SC2MPro inhibitors with ultra-high antiviral potency.

Original languageEnglish (US)
Pages (from-to)942-948
Number of pages7
Issue number6
StatePublished - Mar 18 2021


  • 3C-like protease
  • COVID-19
  • SARS-CoV-2
  • antivirals
  • main protease
  • reversible covalent inhibitors

ASJC Scopus subject areas

  • Drug Discovery
  • General Pharmacology, Toxicology and Pharmaceutics
  • Molecular Medicine
  • Biochemistry
  • Pharmacology
  • Organic Chemistry


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