Severe acute respiratory syndrome coronavirus‐2 is the etiological agent of the ongoing pandemic of coronavirus disease‐2019, a multi‐organ disease that has triggered an unprecedented global health and economic crisis. The virally encoded 3C‐like protease (3CL(pro)), which is named after picornaviral 3C protease (3C(pro)) due to their similarities in substrate recognition and enzymatic activity, is essential for viral replication and has been considered as the primary drug target. However, information regarding the cellular substrates of 3CL(pro) and its interaction with the host remains scarce, though recent work has begun to shape our understanding more clearly. Here we summarized and compared the mechanisms by which picornaviruses and coronaviruses have evolved to evade innate immune surveillance, with a focus on the established role of 3C(pro) in this process. Through this comparison, we hope to highlight the potential action and mechanisms that are conserved and shared between 3C(pro) and 3CL(pro). In this review, we also briefly discussed current advances in the development of broad‐spectrum antivirals targeting both 3C(pro) and 3CL(pro).
Innate immune evasion mediated by picornaviral 3C protease: Possible lessons for coronaviral 3C‐like protease?