byThe University of Hong Kong

Discovery of the Mpro/TMPRSS2 bispecific inhibitor with highly potent anti-coronavirus efficacy. Credit:Nature Communications(2025). DOI: 10.1038/s41467-025-60832-z

A team of researchers have discovered a powerful bispecific inhibitor capable of combating all existing human-pathogenic coronaviruses, including those resistant to existing treatments like Paxlovid. This promising inhibitor, named TMP1, offers hope for more effective and resilient treatments against future outbreaks. A patent has been filed for further exploration in clinical applications.

The study's findingswere published inNature Communications.

Over the past two decades, coronaviruses have led to three major outbreaks, including the COVID-19 pandemic. Recently, scientists have discovered new viruses transmitted from animals to humans, which means the risk of another outbreak remains significant. This ongoing threat highlights the urgent need for better ways to prevent and treat these dangerous viruses.

"One promising target for developing anti-coronavirus treatments is TMPRSS2, a host enzyme that the virus uses to enter human cells. However, existing TMPRSS2 inhibitors used to treat infected patients, such as camostat, have limitations. They are not easily absorbed when taken orally and are quickly broken down in the body, which reduces their effectiveness," explained Professor Chu Hin, Gallant Ho Outstanding Young Professor and Associate Professor in the Department of Microbiology, at LKS Faculty of Medicine of the University of Hong Kong (HKUMed).

Another appealing antiviral target is coronavirus Mpro, which is essential for the virus to replicate. Paxlovid, a drug developed to target SARS-CoV-2 Mpro, has shown strong antiviral potency. But Professor Chu remarked, "The virus can mutate rapidly, leading to variants that are resistant to current drugs, making treatment more challenging."

To overcome these challenges, a research team from the Department of Microbiology, School of Clinical Medicine, HKUMed, and the InnoHK Center for Virology, Vaccinology and Therapeutics (CVVT), in collaboration with Sichuan University, aimed to develop an orally available inhibitor that can simultaneously target the coronavirus Mproand the host TMPRSS2, providing bispecific protection to coronavirus infections with high potency.

Using a new chemical synthesis approach, the research team screened for potent small molecules capable of suppressing the enzymatic activity of SARS-CoV-2 Mproand TMPRSS2. The most promising candidates from the primary screening were chemically optimized to produce a new bispecific inhibitor, TMP1, which was further tested to assess its stability in the body, antiviral effectiveness and sensitivity to drug-resistant mutants.

Professor Chu elaborated, "Our results showed that TMP1, the new bispecific inhibitor, has broad-spectrum antiviral efficacy against all known human-pathogenic coronaviruses, including the highly pathogenic SARS-CoV-2, SARS-CoV-1 and MERS-CoV. Additionally, TMP1 was able to protect hamsters from SARS-CoV-2 transmission.

"TMP1 binds to the enzymatic pocket of Mproat distinct mechanisms when compared with existing drugs like Nirmatrelvir. This suggests that it can potentially overcome some forms of drug resistance. In fact, TMP1 demonstrated robust protection against Paxlovid-resistant SARS-CoV-2 mutants in infected cells and animals."

This study is the first to demonstrate that potent, broad-spectrum protection against coronavirus infections can be achieved by simultaneous targeting of both Mproand TMPRSS2.

"Unlike conventional mono-target antiviral drugs, the bispecific approach opens new avenues for therapeutic design," said Professor Chu. "It paves the way for the development of next-generation antivirals that are not only more effective but also less prone to resistance."

More information: Huiping Shuai et al, An orally available M pro /TMPRSS2 bispecific inhibitor with potent anti-coronavirus efficacy in vivo, Nature Communications (2025). DOI: 10.1038/s41467-025-60832-z Journal information: Nature Communications

Provided by The University of Hong Kong