HKUMed-Tsinghua research team has developed MB-32, a first-in-class broad-spectrum small-molecule antiviral drug candidate, which effectively blocks infection by SARS-CoV-2 and its variants. The research is led by (from left, back row) Professor Chen Zhiwei, Professor Chu Hin and (middle front) Dr Liu Li.
The on-going evolution of SARS-CoV-2, particularly the rapid emergence of the Omicron variant and its sub-lineages, has weakened the effectiveness of existing vaccines and antiviral drugs, underscoring the potential risk of future coronavirus pandemics. In response, a joint research team from the LKS Faculty of Medicine of the University of Hong Kong (HKUMed) and the School of Pharmaceutical Sciences of Tsinghua University has developed MB-32, a novel broad-spectrum small-molecule antiviral drug candidate. By targeting ACE2—a key receptor on the surface of human cells—MB-32 blocks coronavirus entry while preserving ACE2's normal physiological functions, offering a new host-targeting strategy that is less vulnerable to viral mutations. The findings were published in the international journal Nature Communications [link to the publication].
Professor Chen Zhiwei, Chair Professor of Immunology and Immunotherapy and Suen Chi-Sun Professor in Clinical Science in the Department of Microbiology, School of Clinical Medicine, HKUMed, noted that most currently available antivirals act on viral proteins, such as proteases or polymerases, making them susceptible to resistance when the virus mutates. In contrast, many human- and animal-derived coronaviruses, including the 2003 SARS virus and SARS-CoV-2, must bind to the human ACE2 receptor via their spike proteins to enter cells. 'By choosing ACE2 as the drug target, we can bypass many of the constraints imposed by viral evolution and adopt a strategy of "meeting changes with constancy",' he said.
A broad-spectrum drug candidate identified from a 20,000-compound screen
Through high-throughput screening of more than 20,000 small-molecule compounds, the team identified MB-32 as the lead candidate followed by multiple rounds of medicinal-chemistry optimisation. Experimental data showed that MB-32 potently inhibits infection by multiple SARS-CoV-2 variants —including Alpha, Delta and several Omicron subvariants—as well as the 2003 SARS-CoV and related bat- and pangolin-derived coronaviruses, demonstrating broad-spectrum antiviral activity. In contrast, MB-32 showed no measurable effect on viruses that do not rely on ACE2 for cell entry, highlighting its target-specific mechanism of action.
Instead of acting directly on the virus, MB-32 binds to a specific site on the ACE2 receptor and induces a conformational change that prevents the viral spike protein from engaging ACE2. First author Dr Liu Li explained, 'It is like changing the shape of a receptor's "lockhole" so that the virus, acting as a "key", can no longer fit, thereby blocking infection at the point of entry. ACE2 also plays a critical role in regulating blood pressure and maintaining cardiovascular homeostasis. Importantly, MB-32 does not impair ACE2's enzymatic activity, indicating that it can prevent viral infection while preserving normal physiological functions, thus supporting a favourable efficacy-safety balance.'
Animal studies show prevention of infection and interruption of transmission
The research team evaluated MB-32 in ACE2-transgenic mouse and hamster models of SARS-CoV-2 infection. Intranasal administration rapidly achieved effective drug concentrations in the respiratory tract, and prophylactic dosing prior to viral challenge markedly reduced lung viral loads and mitigated tissue damage. In contact-transmission models, MB-32 effectively prevented virus spread from infected to uninfected animals, supporting its potential to interrupt transmission chains. Strikingly, MB-32-treated mice infected with SARS-CoV-2 achieved a 100% survival rate, while all mice in the untreated control group succumbed to the infection, underscoring the candidate's strong therapeutic potential.
Preliminary safety assessments revealed that MB-32 caused no obvious adverse effects on blood pressure, heart rate or electrocardiographic parameters in animal models. The researchers further noted that intranasal administration allows the drug to be concentrated within the respiratory tract, the primary site of coronavirus entry, thereby limiting systemic exposure. This reduces the likelihood of off-target effects and makes MB-32 a promising option for both preventing infection and halting transmission.
First-in-class ACE2-targeting small molecule advancing towards clinical studies
The investigators believe that MB-32 represents a first-in-class small-molecule antiviral drug candidate that directly targets ACE2. It offers a new treatment option for SARS-CoV-2 infection and establishes a frontline defence against future coronaviruses. Professor Chen noted that the next steps will include detailed structural characterisation of the MB-32-ACE2 interaction, further optimisation of the drug properties, and advancing MB-32 through preclinical and clinical studies.
About the research team
The study was jointly led by Professor Chen Zhiwei, Chair Professor of Immunology and Immunotherapy, and Suen Chi-Sun Professor in Clinical Science; Professor Chu Hin, Associate Professor and Gallant Ho Outstanding Young Professor; and Dr Liu Li from the Department of Microbiology, School of Clinical Medicine, HKUMed, and Professor Liu Gang, Tenured Professor of the School of Pharmaceutical Sciences, Tsinghua University.
Acknowledgements
The work was supported by multiple funding sources, including the Key Program of the National Natural Science Foundation of China; the Health and Medical Research Fund, and the Research Grants Council of Hong Kong.
