9ir8
CCoV-HuPn-2018 3CL protease (3CLpro) in complex with compound 6
Structural highlights
FunctionA0A8F2ZG71_9ALPC Forms a primer, NSP9-pU, which is utilized by the polymerase for the initiation of RNA chains. Interacts with ribosome signal recognition particle RNA (SRP). Together with NSP8, suppress protein integration into the cell membrane, thereby disrupting host immune defenses.[ARBA:ARBA00043928] Nsp7-nsp8 hexadecamer may possibly confer processivity to the polymerase, maybe by binding to dsRNA or by producing primers utilized by the latter.[ARBA:ARBA00002928] RNA-directed RNA polymerase that catalyzes the transcription of viral genomic and subgenomic RNAs. Acts in complex with nsp7 and nsp8 to transcribe both the minus and positive strands of genomic RNA. The kinase-like NiRAN domain of NSP12 attaches one or more nucleotides to the amino terminus of NSP9, forming a covalent RNA-protein intermediate that serves as transcription/replication primer. Subgenomic RNAs (sgRNAs) are formed by discontinuous transcription: The polymerase has the ability to pause at transcription-regulating sequences (TRS) and jump to the leader TRS, resulting in a major deletion. This creates a series of subgenomic RNAs that are replicated, transcribed and translated. In addition, Nsp12 is a subunit of the viral RNA capping enzyme that catalyzes the RNA guanylyltransferase reaction for genomic and sub-genomic RNAs. Subsequently, the NiRAN domain transfers RNA to GDP, and forms the core cap structure GpppA-RNA.[ARBA:ARBA00043918] The papain-like proteinase 1 (PLP1) and papain-like proteinase 2 (PLP2) are responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PLP2 possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. PLP2 also antagonizes innate immune induction of type I interferon by blocking the nuclear translocation of host IRF-3.[ARBA:ARBA00025562] The replicase polyprotein of coronaviruses is a multifunctional protein: it contains the activities necessary for the transcription of negative stranded RNA, leader RNA, subgenomic mRNAs and progeny virion RNA as well as proteinases responsible for the cleavage of the polyprotein into functional products.[ARBA:ARBA00003368] 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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