Rational Design of Hybrid SARS-CoV-2 Main Protease Inhibitors Guided by the Superimposed Cocrystal Structures with the Peptidomimetic Inhibitors GC-376, Telaprevir, and Boceprevir

  • ACS Pharmacol Transl Sci. 2021 Jun 9;4(4):1408-1421. doi: 10.1021/acsptsci.1c00099.
Zilei Xia  1 ,  Michael Sacco  2 ,  Yanmei Hu  1 ,  Chunlong Ma  1 ,  Xiangzhi Meng  3 ,  Fushun Zhang  3 ,  Tommy Szeto  1 ,  Yan Xiang  3 ,  Yu Chen  2 ,  Jun Wang  1
Affiliations
  • 1. Department of Pharmacology and Toxicology, College of Pharmacy, The University of Arizona, Tucson, Arizona 85721, United States.
  • 2. Department of Molecular Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida 33612, United States.
  • 3. Department of Microbiology, Immunology, and Molecular Genetics, University of Texas Health Science Center at San Antonio, San Antonio, Texas 78229, United States.
PMID: 34414360 DOI: 10.1021/acsptsci.1c00099
Abstract

SARS-CoV-2 main protease (Mpro) is a cysteine protease that mediates the cleavage of viral polyproteins and is a validated Antiviral drug target. Mpro is highly conserved among all seven human coronaviruses, with certain Mpro inhibitors having broad-spectrum Antiviral activity. In this study, we designed two hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 based on the superimposed X-ray crystal structures of SARS-CoV-2 Mpro with GC-376, telaprevir, and boceprevir. Both UAWJ9-36-1 and UAWJ9-36-3 showed potent binding and enzymatic inhibition against the Mpro's from SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-OC43, HCoV-NL63, HCoV-229E, and HCoV-HKU1. Cell-based Flip-GFP Mpro assay results show that UAWJ9-36-1 and UAWJ9-36-3 inhibited the intracellular protease activity of SARS-CoV-2 Mpro. In addition, UAWJ9-36-1 and UAWJ9-36-3 had potent Antiviral activity against SARS-CoV-2, HCoV-OC43, HCoV-NL63, and HCoV-229E, with UAWJ9-36-3 being more potent than GC-376 in inhibiting SARS-CoV-2. Selectivity profiling revealed that UAWJ9-36-1 and UAWJ9-36-3 had an improved selectivity index over that of GC-376 against host cysteine proteases calpain I and Cathepsin L, but not Cathepsin K. The X-ray crystal structures of SARS-CoV-2 Mpro with UAWJ9-36-1 and UAWJ9-36-3 were both solved at 1.9 Å, which validated our design hypothesis. Overall, hybrid inhibitors UAWJ9-36-1 and UAWJ9-36-3 are promising candidates to be further developed as broad-spectrum coronavirus antivirals.

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