Over the last few years, the SARS-CoV-2 virus, responsible for COVID-19, has undergone significant changes, evolving from the original wild-type strains to the highly transmissible Omicron variant. Omicron has been particularly concerning due to its ability to evade immune protection from vaccines and monoclonal antibodies developed against earlier strains. A critical player in the virus's life cycle is the main protease (M pro ), also known as NSP5 or 3CL protease, which plays a crucial role in the cleavage and maturation of SARS-CoV-2 proteins within the host cells.
This makes M pro a key target for antiviral drug development. In 2021, the FDA approved nirmatrelvir (NTV) as the first oral antiviral drug targeting M pro , marketed under the brand name Paxlovid. Despite its initial success, some patients treated with NTV have developed mutations in M pro , such as the E166V mutation , making the virus up to 100 times less sensitive to the drug.
Two additional M pro inhibitors, Ensitrelvir (ETV) and Leritrelvir (LTV), have also been approved for use. Importantly, LTV, approved in China in March 2024, does not require co-administration with ritonavir, a drug used with some antivirals to enhance their effectiveness. However, the effectiveness of these drugs against different M pro variants is not fully understood.
In a recent study published in the Quantitative Biology journal, research groups led by Nan Li and Xuefei Li at the Shenzhen Institutes of Advanced Technology (SIAT) a.