New Bispecific Inhibitor Targets Multiple Coronaviruses, Including Resistant Varieties

Researchers have developed a novel bispecific inhibitor capable of effectively combating a broad range of coronaviruses, including variants that show resistance to existing antiviral treatments such as Paxlovid. This promising compound, designated TMP1, represents a significant advancement in the quest for more resilient therapeutic options against coronaviruses, especially in light of ongoing outbreaks.

The findings of this study were published in Nature Communications, highlighting the urgent need for improved antiviral strategies as the threat of future animal-to-human coronavirus transmissions persists. Over the past two decades, coronaviruses have been responsible for three major outbreaks, underscoring the necessity for enhanced prevention and treatment methodologies.

Professor Chu Hin, an associate professor at the University of Hong Kong's Department of Microbiology, pointed out that a key target for developing anti-coronavirus treatments is TMPRSS2, an enzyme that facilitates the entry of viruses into human cells. Existing TMPRSS2 inhibitors, while useful, have limitations related to their oral absorption and rapid breakdown in the body, diminishing their effectiveness.

Another target of interest is the coronavirus main protease (Mpro), vital for viral replication. Although Paxlovid has demonstrated strong antiviral properties against SARS-CoV-2 Mpro, the rapid mutation rate of the virus poses challenges, leading to the emergence of resistant variants.

To address these challenges, the research team from the University of Hong Kong, in collaboration with Sichuan University, sought to create an orally bioavailable inhibitor that could simultaneously target both Mpro and TMPRSS2. This bispecific approach aims to provide comprehensive protection against coronavirus infections with enhanced potency.

Utilizing a novel chemical synthesis technique, the researchers screened for small molecules that effectively inhibit the enzymatic activities of both SARS-CoV-2 Mpro and TMPRSS2. The most promising candidates underwent chemical optimization to yield TMP1, which was then evaluated for its stability, antiviral efficacy, and effectiveness against drug-resistant variants.

Results indicated that TMP1 exhibits broad-spectrum antiviral activity against all known human-pathogenic coronaviruses, including SARS-CoV-2, SARS-CoV-1, and MERS-CoV. In preclinical studies, TMP1 successfully protected hamsters from SARS-CoV-2 transmission.

Moreover, TMP1's unique binding mechanism to the Mpro enzymatic pocket differs from that of existing treatments, suggesting its potential to bypass certain forms of drug resistance. Notably, TMP1 demonstrated robust protection against SARS-CoV-2 variants resistant to Paxlovid in both cell and animal models.

This research is groundbreaking as it illustrates that effective, broad-spectrum protection against coronaviruses can be achieved through the simultaneous targeting of both Mpro and TMPRSS2. This innovative bispecific approach offers a new avenue for the development of next-generation antiviral therapies that could be more effective and less susceptible to resistance.

In conclusion, the development of TMP1 marks a significant step forward in the fight against coronaviruses, providing hope for more effective treatment options in the future.