9ir9
SARS-CoV-2 3CL protease (3CLpro) in complex with compound 6
Structural highlights
FunctionR1A_SARS2 Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein.[UniProtKB:P0C6X7] Inhibits host translation by interacting with the 40S ribosomal subunit. The nsp1-40S ribosome complex further induces an endonucleolytic cleavage near the 5'UTR of host mRNAs, targeting them for degradation. Viral mRNAs are not susceptible to nsp1-mediated endonucleolytic RNA cleavage thanks to the presence of a 5'-end leader sequence and are therefore protected from degradation. By suppressing host gene expression, nsp1 facilitates efficient viral gene expression in infected cells and evasion from host immune response.[UniProtKB:P0C6X7] May play a role in the modulation of host cell survival signaling pathway by interacting with host PHB and PHB2. Indeed, these two proteins play a role in maintaining the functional integrity of the mitochondria and protecting cells from various stresses.[UniProtKB:P0C6X7] Responsible for the cleavages located at the N-terminus of the replicase polyprotein. In addition, PL-PRO possesses a deubiquitinating/deISGylating activity and processes both 'Lys-48'- and 'Lys-63'-linked polyubiquitin chains from cellular substrates. Participates together with nsp4 in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication. Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3. Prevents also host NF-kappa-B signaling.[UniProtKB:P0C6X7] Participates in the assembly of virally-induced cytoplasmic double-membrane vesicles necessary for viral replication.[UniProtKB:P0C6X7] Cleaves the C-terminus of replicase polyprotein at 11 sites. Recognizes substrates containing the core sequence [ILMVF]-Q-|-[SGACN]. Also able to bind an ADP-ribose-1-phosphate (ADRP).[UniProtKB:P0C6X7] Plays a role in the initial induction of autophagosomes from host reticulum endoplasmic. Later, limits the expansion of these phagosomes that are no longer able to deliver viral components to lysosomes.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp8 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] Forms a hexadecamer with nsp7 (8 subunits of each) that may participate in viral replication by acting as a primase. Alternatively, may synthesize substantially longer products than oligonucleotide primers.[UniProtKB:P0C6X7] May participate in viral replication by acting as a ssRNA-binding protein.[UniProtKB:P0C6X7] Plays a pivotal role in viral transcription by stimulating both nsp14 3'-5' exoribonuclease and nsp16 2'-O-methyltransferase activities. Therefore plays an essential role in viral mRNAs cap methylation.[UniProtKB:P0C6X7] 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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