9or4
Crystal structure of SARS-CoV2 PLpro in complex with a covalent inhibitor
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 COVID-19 pandemic led to numerous initiatives to create antiviral medications and vaccines for the treatment and prevention of infections. However, the need remains for new therapies with distinct mechanisms of action from current treatment of COVID-19 infections as well as for future pandemic preparedness. SARS-CoV-2 papain-like protease (PLpro) is a cysteine protease that cleaves the viral polyprotein and possesses deubiquitylase (DUB) and deISGylase activity that can act on host proteins. Here, we report the structure-guided development of covalent inhibitors of SARS-CoV-2 PLpro that possess low nanomolar to subnanomolar antiviral activity in cell assays and inhibit viral replication in a mouse model of SARS-CoV-2 infection. The most potent inhibitors contain N-propargylamide electrophiles, a relatively inert warhead not typically featured in covalent protease inhibitors. These findings provide a foundation for further discovery and optimization of covalent PLpro inhibitors that could lead to future antiviral therapeutics. Structure-Guided Design of Potent and Selective Covalent Inhibitors Targeting the SARS-CoV-2 Papain-like Protease.,Sharafi M, Teh WP, Green J, Charifson PS, Wang J, Pemberton OA, Nevins AM, Lye M, Liu X, Varca AC, Owen CD, Morsheimer K, Wacquiez A, Dawson C, Steuber C, Smith J, Girardi NM, Magin RS, Marto JA, Saeed M, Davey RA, Hardee D, Ng TI, Namchuk MN, Buhrlage SJ J Med Chem. 2026 Jan 20. doi: 10.1021/acs.jmedchem.5c01973. PMID:41557701[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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