2. Academic Validation
  3. Targeted protein degraders of SARS-CoV-2 Mpro are more active than enzymatic inhibition alone with activity against nirmatrelvir resistant virus

Targeted protein degraders of SARS-CoV-2 Mpro are more active than enzymatic inhibition alone with activity against nirmatrelvir resistant virus

  • Commun Med (Lond). 2025 Apr 26;5(1):140. doi: 10.1038/s43856-025-00863-1.
Baolong Pan 1 2,  Simon J Mountford 1,  Maki Kiso 3 4,  Danielle E Anderson 5 6,  Georgina Papadakis 5,  Kate E Jarman 7 8,  Danielle R Tilmanis 7 8,  Belinda Maher 9 10,  Thomas Tran 5,  Jake Shortt 9 10,  Seiya Yamayoshi 3 4 11 12,  Yoshihiro Kawaoka 3 4 11 13,  Philip E Thompson # 1,  Sam A Greenall # 9,  Nadia Warner # 14
Affiliations

Affiliations

  • 1 Medicinal Chemistry, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Australia.
  • 2 Department of Chemistry, Massachusetts Institute of Technology, Cambridge, USA.
  • 3 Division of Virology, Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
  • 4 The University of Tokyo Pandemic Preparedness, Infection and Advanced Research Center, Tokyo, Japan.
  • 5 Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
  • 6 Department of Microbiology and Immunology, The University of Melbourne at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia.
  • 7 The Walter and Eliza Hall Institute, Parkville, Australia.
  • 8 Department of Medical Biology, The University of Melbourne, Parkville, Australia.
  • 9 Department of Medicine, School of Clinical Sciences, Monash University, Clayton, Australia.
  • 10 Monash Haematology, Monash Health, Clayton, Australia.
  • 11 International Research Center for Infectious Diseases, Institute of Medical Science, University of Tokyo, Tokyo, Japan.
  • 12 The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
  • 13 Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison, Madison, USA.
  • 14 Victorian Infectious Diseases Reference Laboratory, Royal Melbourne Hospital at The Peter Doherty Institute for Infection and Immunity, Melbourne, Australia. nadia.warner@mh.org.au.
  • # Contributed equally.
PMID: 40287552 DOI: 10.1038/s43856-025-00863-1
Abstract

Background: Effective Antiviral therapy is lacking for most viral infections, and when available, is frequently compromised by the selection of resistance. Targeted protein degraders could provide an avenue to more effective antivirals, able to overcome the selection of resistance. The aim of this study was to determine whether adaptation of SARS-CoV-2 main protease (Mpro, also described as chymotrypsin-like protease (3CLpro) or non-structural protein 5 (Nsp5)) inhibitors into degraders leads to increased Antiviral activity, including activity against resistant virus.

Methods: We adapted the clinically approved Mpro inhibitor nirmatrelvir into a panel of degraders. Size-matched non-degrading controls were also synthesised to discriminate degradation activity from inhibition activity. Degrader activity was confirmed using an inducible Mpro-HiBiT tag expressing cell line. Antiviral activity against both wildtype and nirmatrelvir-resistant virus was performed using Infection of susceptible cell lines.

Results: Here we show three compounds, derived from nirmatrelvir and utilising VHL or IAP ubiquitin Ligase recruiters, capable of degrading Mpro protein in a concentration, time and Proteasome dependent fashion. These compounds also degrade nirmatrelvir-resistant mutant Mpro. The most potent of these compounds possesses enhanced Antiviral activity against multiple wildtype SARS-CoV-2 strains and nirmatrelvir-resistant strains compared to non-degrading controls.

Conclusions: This work demonstrates the feasibility of generating degraders from viral protein inhibitors, and confirms that degraders possess higher Antiviral potency and activity against resistant virus, compared to size matched non-degrading enzymatic inhibitors. These findings further support the development of targeted viral protein degraders as Antiviral drugs, which may lead to more effective Antiviral therapies for the future.

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