Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

  • J Med Chem. 2024 Apr 25;67(8):6495-6507. doi: 10.1021/acs.jmedchem.3c02416.
Yugendar R Alugubelli  1 ,  Jing Xiao  1 ,  Kaustav Khatua  1 ,  Sathish Kumar  2 ,  Long Sun  3 ,  Yuying Ma  1 ,  Xinyu R Ma  1 ,  Veerabhadra R Vulupala  1 ,  Sandeep Atla  1 ,  Lauren R Blankenship  1 ,  Demonta Coleman  1 ,  Xuping Xie  3 ,  Benjamin W Neuman  2  4 ,  Wenshe Ray Liu  1  5  6  7 ,  Shiqing Xu  1  8
Affiliations
  • 1. Texas A&M Drug Discovery Center, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
  • 2. Department of Biology, Texas A&M University, College Station, Texas 77843, United States.
  • 3. Department of Biochemistry & Molecular Biology, The University of Texas Medical Branch, Galveston, Texas 77555, United States.
  • 4. Texas A&M Global Health Research Complex, Texas A&M University, College Station, Texas 77843, United States.
  • 5. Department of Biochemistry and Biophysics, Texas A&M University, College Station, Texas 77843, United States.
  • 6. Institute of Biosciences and Technology and Department of Translational Medical Sciences, College of Medicine, Texas A&M University, Houston, Texas 77030, United States.
  • 7. Department of Molecular and Cellular Medicine, College of Medicine, Texas A&M University, College Station, Texas 77843, United States.
  • 8. Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, Texas 77843, United States.
PMID: 38608245 DOI: 10.1021/acs.jmedchem.3c02416
Abstract

We have witnessed three coronavirus (CoV) outbreaks in the past two decades, including the COVID-19 pandemic caused by SARS-CoV-2. Main protease (MPro), a highly conserved protease among various CoVs, is essential for viral replication and pathogenesis, making it a prime target for Antiviral drug development. Here, we leverage proteolysis targeting chimera (PROTAC) technology to develop a new class of small-molecule antivirals that induce the degradation of SARS-CoV-2 MPro. Among them, MPD2 was demonstrated to effectively reduce MPro protein levels in 293T cells, relying on a time-dependent, CRBN-mediated, and proteasome-driven mechanism. Furthermore, MPD2 exhibited remarkable efficacy in diminishing MPro protein levels in SARS-CoV-2-infected A549-ACE2 cells. MPD2 also displayed potent Antiviral activity against various SARS-CoV-2 strains and exhibited enhanced potency against nirmatrelvir-resistant viruses. Overall, this proof-of-concept study highlights the potential of targeted protein degradation of MPro as an innovative approach for developing antivirals that could fight against drug-resistant viral variants.

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