2. Academic Validation
  3. An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

An orally bioavailable SARS-CoV-2 main protease inhibitor exhibits improved affinity and reduced sensitivity to mutations

  • Sci Transl Med. 2024 Mar 13;16(738):eadi0979. doi: 10.1126/scitranslmed.adi0979.
Michael Westberg 1 2 3,  Yichi Su 1 4,  Xinzhi Zou 5,  Pinghan Huang 6,  Arjun Rustagi 7,  Jaishree Garhyan 8,  Puja Bhavesh Patel 8,  Daniel Fernandez 9 10,  Yan Wu 5,  Chenzhou Hao 1,  Chieh-Wen Lo 7,  Marwah Karim 7,  Lin Ning 1,  Aimee Beck 7,  Panatda Saenkham-Huntsinger 6,  Vivian Tat 11,  Aleksandra Drelich 6,  Bi-Hung Peng 12,  Shirit Einav 7 13 14,  Chien-Te K Tseng 6 11 12,  Catherine Blish 7 14,  Michael Z Lin 1 5 15
Affiliations

Affiliations

  • 1 Department of Neurobiology, Stanford University, Stanford, CA 94305, USA.
  • 2 Department of Chemistry, Aarhus University, 8000 Aarhus C, Denmark.
  • 3 Interdisciplinary Nanoscience Center (iNANO), Aarhus University, 8000 Aarhus C, Denmark.
  • 4 Institute for Translational Brain Research, State Key Laboratory of Medical Neurobiology, MOE Frontiers Center for Brain Science, Fudan University, Shanghai 200032, China.
  • 5 Department of Bioengineering, Stanford University, Stanford, CA 94305, USA.
  • 6 Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 7 Department of Medicine, Stanford University, Stanford, CA 94305, USA.
  • 8 Stanford In Vitro Biosafety Level 3 Service Center, Stanford University, Stanford, CA 94305, USA.
  • 9 Program in Chemistry, Engineering, and Medicine for Human Health (ChEM-H), Stanford University, Stanford, CA 94305, USA.
  • 10 Sarafan ChEM-H, Macromolecular Structure Knowledge Center, Stanford University, Stanford, CA 94305, USA.
  • 11 Department of Pathology, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 12 Department of Neuroscience, Cell Biology, and Anatomy, University of Texas Medical Branch, Galveston, TX 77555, USA.
  • 13 Department of Microbiology and Immunology, Stanford University, Stanford, CA 94305, USA.
  • 14 Chan Zuckerberg Biohub, San Francisco, CA 94158, USA.
  • 15 Department of Chemical and Systems Biology, Stanford University, Stanford, CA 94305, USA.
PMID: 38478629 DOI: 10.1126/scitranslmed.adi0979
Abstract

Inhibitors of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) main protease (Mpro) such as nirmatrelvir (NTV) and ensitrelvir (ETV) have proven effective in reducing the severity of COVID-19, but the presence of resistance-conferring mutations in sequenced viral genomes raises concerns about future drug resistance. Second-generation oral drugs that retain function against these mutants are thus urgently needed. We hypothesized that the covalent hepatitis C Virus Protease Inhibitor boceprevir (BPV) could serve as the basis for orally bioavailable drugs that inhibit SARS-CoV-2 Mpro more efficiently than existing drugs. Performing structure-guided modifications of BPV, we developed a picomolar-affinity inhibitor, ML2006a4, with Antiviral activity, oral pharmacokinetics, and therapeutic efficacy similar or superior to those of NTV. A crucial feature of ML2006a4 is a derivatization of the ketoamide reactive group that improves cell permeability and oral bioavailability. Last, ML2006a4 was found to be less sensitive to several mutations that cause resistance to NTV or ETV and occur in the natural SARS-CoV-2 population. Thus, anticipatory design can preemptively address potential resistance mechanisms to expand future treatment options against coronavirus variants.

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