2. Academic Validation
  3. Discovery of First-in-Class PROTAC Degraders of SARS-CoV-2 Main Protease

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

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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