Viral infectious diseases have been seriously affecting human life and health. SARS-CoV-2 was the pathogen that caused Coronavirus Disease 2019 (COVID-19), and the impact of COVID-19 is still existing. Enterovirus 71 (EV71) is the primary pathogen of hand, foot, and mouth disease (HFMD), and no effective direct-acting antiviral drugs targeting EV71 has been approved yet. Innate antiviral strategies play an important role in preventing virus infections depending on the powerful immune regulatory system of body, while viruses have evolved to exploit diverse methods to overcome immune response. Viral proteases, which are known in cleaving viral polyproteins, have also been found to modulate the innate immunity of host cells, thereby promoting viral proliferation. Herein, we reviewed the current development of SARS-CoV-2 3CL, PL, and EV71 3C and 2A, mainly including structure, function, modulation of immune response, and inhibitors of these four proteases, to further deepen the understanding of viral pathogenesis and provide a new perspective for subsequent corresponding drug development.
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