Picornaviral 3C protease inhibitors and the dual 3C protease/coronaviral 3C-like protease inhibitors

Importance of the field: Picornaviruses are small non-enveloped RNA viruses with genomic RNA of 7500 - 8000 nuclecitides, whereas coronaviruses (CoV) are RNA viruses with larger genome of 27 - 32 kb. Both types of viruses translate their genetic information into polyprotein precursors that are processed by virally encoded 3C proteases (3C(pro)) and 3C-like proteases (3CL(pro)), respectively, to generate functional viral proteins. The most studied human rhinoviruses (HRV) belonging to picornaviridae family are the main etiologic agents of the common cold. Due to lack of effective drugs, 3C(pro) has served as an excellent target for anti-viral intervention and considerable efforts have been made in the development of inhibitors. Interestingly, the inhibitors of 3C(pro) cannot inhibit 3CL(pro) potently without modification due to subtle differences in their active-site structures, but a group of common inhibitors against 3C(pro) and 3CL(pro) were found recently. Areas covered in this review. The inhibitors against 3C(pro) reported in the literatures and patents, with a focus on those inhibiting HRV and the dual picornaviral 3C(pro)/coronaviral 3CL(pro) inhibitors, are summarized in this review. What the readers will gain: Readers will rapidly gain an overview of the individual and dual 3C(pro) inhibitors and the structural basis for discriminating them. Take home message: In the future, more selective potent inhibitors against each protease and dual inhibitors against both proteases can be further developed to treat the diseases caused by picornaviruses and CoV.