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Crystal structure of IBV 3CL protease (3CLpro) in complex with compound 8
Structural highlights
FunctionR1A_IBVB The papain-like proteinase (PL-PRO) is responsible for the cleavages located at the N-terminus of replicase polyprotein. Activity of PL-PRO is dependent on zinc (By similarity). The main proteinase 3CL-PRO is responsible for the majority of cleavages as it cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Inhibited by the substrate-analog Cbz-Val-Asn-Ser-Thr-Leu-Gln-CMK.[PROSITE-ProRule:PRU00772] The peptide p16 might be involved in the EGF signaling pathway. Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter. Nsp9 is a ssRNA-binding protein. Publication Abstract from PubMedRecurrence of coronavirus outbreaks and zoonotic origins of human coronaviruses underscore the importance of developing pan-coronavirus antivirals. The highly conserved 3C-like protease (3CL(pro)) in coronaviruses, together with the well-established druggability, makes it an ideal target for broad-spectrum antiviral therapeutics. Here, the inhibitory activity of approved 3CL(pro) inhibitors, including nirmatrelvir, ensitrelvir, and simnotrelvir, against fifteen 3CL(pro)s is first reported by enzymatic assays. Despite their potent inhibition toward 3CL(pro)s of beta-CoVs, these inhibitors show reduced potency against 3CL(pro)s from the other three genera, particularly against two newly identified human coronaviruses (alpha-CCoV-HuPn-2018 and delta-PDCoV). In this context, continued efforts in structure-based optimization of nirmatrelvir lead to the identification of compound 8 that potently inhibits a panel of 32 3CL(pro)s across all subgenera (IC(50)s: 19-146 nm), with an IC(50) value of 61 and 81 nm against alpha-CCoV-HuPn-2018 and delta-PDCoV 3CL(pro)s, respectively. Moreover, it effectively inhibits nirmatrelvir-resistant 3CL(pro) mutants and demonstrates broad-spectrum antiviral efficacy in cells. These findings suggest an important rule that a small, non-cyclic P2 segment and a P4 segment with a suitable size are preferred by the design of ultra-broad-spectrum 3CL(pro) inhibitors, and provide a proof-of-concept guide for developing broad-spectrum antivirals as potential pan-CoV therapeutics. Structure-Based Development of Ultra-Broad-Spectrum 3C-Like Protease Inhibitors.,Su H, Nie T, Chen G, Xiong M, Zhang Y, Wu G, You M, Xie H, He J, Xiong Y, Hu H, Zhao W, Li M, Xiao G, Zhang L, Xu Y Adv Sci (Weinh). 2025 Dec 12:e12342. doi: 10.1002/advs.202512342. PMID:41388583[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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