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An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo

Huiping Shuai1, Jingxin Qiao2, Chaemin Yoon1

  • 1State Key Laboratory of Emerging Infectious Diseases, Department of Microbiology, School of Clinical Medicine, Li Ka Shing Faculty of Medicine, The University of Hong Kong, and Pandemics Research Alliance Unit at The University of Hong Kong, Hong Kong Special Administrative Region, China.

Nature Communications
|July 16, 2025
PubMed

Insights

A new oral antiviral, TMP1, targets both Mpro and TMPRSS2 proteases to combat coronaviruses. This broad-spectrum inhibitor shows promise against SARS-CoV-2 variants and other pathogenic human coronaviruses.

Area of Science:

  • Virology
  • Drug Discovery
  • Molecular Biology

Background:

  • Coronaviruses have caused significant global endemics (e.g., SARS, MERS, COVID-19).
  • Emerging zoonotic coronaviruses pose a continuous threat of future outbreaks.
  • Broad-spectrum antiviral therapies are crucial for pandemic preparedness.

Purpose of the Study:

  • To develop an orally available bispecific inhibitor targeting key coronavirus enzymes.
  • To evaluate the broad-spectrum antiviral activity of the inhibitor against various coronaviruses.
  • To investigate the therapeutic potential and transmission-blocking capabilities of the novel compound.

Main Methods:

  • Development of a bispecific inhibitor (TMP1) targeting viral Mpro and host TMPRSS2.
  • In vitro testing against SARS-CoV-2 variants and other human coronaviruses.
  • In vivo efficacy studies in K18-hACE2 transgenic mice, hDPP4 knock-in mice, and golden Syrian hamsters.
  • Structural and mutagenesis studies to elucidate drug-target interactions.
  • Assessment of activity against nirmatrelvir-resistant SARS-CoV-2 mutants.

Main Results:

  • TMP1 demonstrated broad-spectrum antiviral activity against multiple coronaviruses in vitro.
  • The inhibitor provided cross-protection against SARS-CoV-1, SARS-CoV-2, and MERS-CoV in vivo.
  • TMP1 efficiently abrogated SARS-CoV-2 transmission in animal models.
  • Structural studies confirmed direct interaction with Mpro and TMPRSS2.
  • TMP1 inhibited infection by nirmatrelvir-resistant SARS-CoV-2 escape mutants.

Conclusions:

  • Bispecific Mpro/TMPRSS2 inhibition represents a promising antiviral strategy.
  • TMP1 exhibits significant therapeutic and prophylactic potential against human-pathogenic and emerging coronaviruses.
  • The drug's oral availability and broad-spectrum activity enhance its pandemic preparedness value.

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