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Published on: October 11, 2013
An orally available Mpro/TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo
Hin Chu1, Huiping Shuai1, Jingxin Qiao2
1The University of Hong Kong.
Abstract:
Coronaviruses have caused three major endemics in the past two decades. Alarmingly, recent identification of novel zoonotic coronaviruses that caused human infections suggests the risk of future coronavirus outbreak caused by spillover infection from animal reservoirs remains high1,2. Therefore, development of novel therapeutic options with broad-spectrum anti-coronavirus activities are urgently needed. Here, we develop an orally-available bispecific inhibitor, TMP1, which simultaneously targets key coronavirus replication protease Mpro and the essential airway protease TMPRSS23,4. TMP1 shows broad-spectrum protection not only against different SARS-CoV-2 variants but also against multiple human-pathogenic coronaviruses in vitro. By using the K18-hACE2 transgenic mouse, hDPP4 knock-in mouse and golden Syrian hamster models, we demonstrate TMP1 cross-protects against highly-pathogenic coronaviruses (SARS-CoV-1, SARS-CoV-2 and MERS-CoV) in vivo and efficiently abrogates SARS-CoV-2 transmission. Through structural and mutagenesis studies, we confirmed the direct interaction of TMP1 with Mpro and TMPRSS2, and pinpoint the key sites of interactions. Importantly, TMP1 inhibits the infection of nirmatrelvir-resistant SARS-CoV-2 escape mutants. Together, our findings demonstrate the antiviral potential of the novel bispecific Mpro/TMPRSS2 antiviral design against human-pathogenic coronaviruses and other emerging coronaviruses.
Insights
A new drug, TMP1, targets two key viral proteases to combat coronaviruses. This orally available, bispecific inhibitor shows broad-spectrum activity against multiple coronaviruses, including resistant strains, offering hope for future outbreaks.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- Coronaviruses have caused significant global health crises, necessitating novel broad-spectrum antiviral therapies.
- The risk of future zoonotic coronavirus spillover events remains high, emphasizing the need for effective countermeasures.
Purpose of the Study:
- To develop an orally available, bispecific inhibitor targeting key viral and host proteases involved in coronavirus replication.
- To evaluate the broad-spectrum antiviral activity and therapeutic potential of the novel inhibitor against various human-pathogenic coronaviruses.
Main Methods:
- Development of TMP1, a bispecific inhibitor targeting coronavirus Mpro and human TMPRSS2.
- In vitro and in vivo efficacy studies using various coronavirus strains and animal models (K18-hACE2, hDPP4, golden Syrian hamster).
- Structural and mutagenesis studies to elucidate drug-target interactions.
Main Results:
- TMP1 demonstrated broad-spectrum activity against SARS-CoV-2 variants and other human coronaviruses in vitro.
- In vivo studies showed TMP1 cross-protection against SARS-CoV-1, SARS-CoV-2, and MERS-CoV, and abrogated SARS-CoV-2 transmission.
- TMP1 effectively inhibited nirmatrelvir-resistant SARS-CoV-2 escape mutants.
Conclusions:
- The bispecific Mpro/TMPRSS2 inhibitor design shows significant potential as a therapeutic strategy against human-pathogenic and emerging coronaviruses.
- TMP1 represents a promising orally available antiviral option for combating current and future coronavirus threats.
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