SARS-CoV-2 main protease inhibitors: What is moving in the field of peptides and peptidomimetics?

The COVID-19 pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is still affecting people worldwide. Despite the good degree of immunological protection achieved through vaccination, there are still severe cases that require effective antivirals. In this sense, two specific pharmaceutical preparations have been marketed already, the RdRp polymerase inhibitor molnupiravir and the main viral protease (Mpro) inhibitor nirmaltrelvir (commercialized as Paxlovid, a combination with ritonavir). Nirmaltrelvir is a peptidomimetic acting as orally available, covalent and reversible inhibitor of SARS-CoV-2 Mpro. The success of this compound has revitalized the search for new peptide and peptidomimetic protease inhibitors. This Highlight collects some selected examples among those recently published in the field of SARS-CoV-2.