8i30 | pdb_00008i30
Crystal structure of the SARS-CoV-2 main protease in complex with 32j
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 PubMedThe SARS-CoV-2 main protease (M(pro), also named 3CL(pro)) is a promising antiviral target against COVID-19 due to its functional importance in viral replication and transcription. Herein, we report the discovery of a series of alpha-ketoamide derivatives as a new class of SARS-CoV-2 M(pro) inhibitors. Structure-activity relationship (SAR) of these compounds was analyzed, which led to the identification of a potent M(pro) inhibitor (27h) with an IC(50) value of 10.9 nM. The crystal structure of M(pro) in complex with 27h revealed that alpha-ketoamide warhead covalently bound to Cys145s of the protease. In an in vitro antiviral assay, 27h showed excellent activity with an EC(50) value of 43.6 nM, comparable to the positive control, Nirmatrelvir. This compound displayed high target specificity for M(pro) against human proteases and low toxicity. It also possesses favorable pharmacokinetic properties. Overall, compound 27h could be a promising lead compound for drug discovery targeting SARS-CoV-2 M(pro) and deserves further in-depth studies. Discovery and structure-activity relationship studies of novel alpha-ketoamide derivatives targeting the SARS-CoV-2 main protease.,Huang C, Zeng R, Qiao J, Quan B, Luo R, Huang Q, Guo N, Li Y, Long X, Ma R, Xia A, Fang Z, Wang Y, Li Y, Zheng Y, Li L, Lei J, Yang S Eur J Med Chem. 2023 Jul 20;259:115657. doi: 10.1016/j.ejmech.2023.115657. PMID:37517202[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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