SARS-CoV-2 Mpro Inhibitors: Achieved Diversity, Developing Resistance and Future Strategies

While the COVID-19 pandemic seems to be on its decline, the unclear impacts of long-COVID cases, breakthrough infections in immunocompromised individuals, vaccine hesitancy, and inhomogeneous health-care accessibility constitute a not to be underestimated threat. These cases, along with pandemic preparedness, ask for an alert identification of new drugs and the optimization of existing drugs as therapeutic treatment options for this and potential future diseases. Mpro inhibitors were identified early on as potent drug candidates against coronaviruses, since they target viable processing machinery within the virus, i.e., the main protease that cleaves the polyproteins encoded by the viral RNA into functional proteins. Different strategies, including reversible and irreversible inhibition as well as allosteric inhibitors, mostly from drug repurposing endeavors, have been explored in the design of potent SARS-CoV-2 Mpro antivirals. Ambitious screening efforts have uttered an outstanding chemical and structural diversity, which has led to half a dozen lead compounds being currently in clinical trials and the emergency FDA approval of ritonavir-boosted nirmatrelvir as a COVID-19 therapeutic. This comprehensive analysis of the achieved inhibitor diversity sorted into irreversible, reversible, and allosteric Mpro binders, along with a discussion of emerging resistance reports and possible evasion strategies, is aimed at stimulating continuing Mpro drug design efforts.