7zqw
From Proteopedia
Structure of the SARS-CoV-1 main protease in complex with AG7404
Structural highlights
FunctionR1A_SARS Multifunctional protein involved in the transcription and replication of viral RNAs. Contains the proteinases responsible for the cleavages of the polyprotein. 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 (PubMed:23035226). May disrupt nuclear pore function by binding and displacing host NUP93 (PubMed:30943371).[1] [2] 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.[3] 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 (PubMed:17692280). Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). Antagonizes innate immune induction of type I interferon by blocking the phosphorylation, dimerization and subsequent nuclear translocation of host IRF3 (PubMed:19369340, PubMed:24622840). Prevents also host NF-kappa-B signaling.[4] [5] [6] [7] [8] Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Alone appears incapable to induce membrane curvature, but together with nsp3 is able to induce paired membranes. Nsp3, nsp4 and nsp6 together are sufficient to form DMV.[9] [10] 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). May cleave host ATP6V1G1 thereby modifying host vacuoles intracellular pH.[PROSITE-ProRule:PRU00772][11] Plays a role in host membrane rearrangement that leads to creation of cytoplasmic double-membrane vesicles (DMV) necessary for viral replication. Nsp3, nsp4 and nsp6 together are sufficient to form DMV (PubMed:24410069). 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 (PubMed:24991833).[12] [13] 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.[14] 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.[15] May participate in viral replication by acting as a ssRNA-binding protein.[16] 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.[17] Publication Abstract from PubMedSevere acute respiratory syndrome coronaviruses 1 and 2 (SARS-CoV-1 and SARS-CoV-2) pose a threat to global public health. The 3C-like main protease (M(pro)), which presents structural similarity with the active site domain of enterovirus 3C protease, is one of the best-characterized drug targets of these viruses. Here we studied the antiviral activity of the orally bioavailable enterovirus protease inhibitor AG7404 against SARS-CoV-1 and SARS-CoV-2 from a structural, biochemical, and cellular perspective, comparing it with the related molecule rupintrivir (AG7800). Crystallographic structures of AG7404 in complex with SARS-CoV-1 M(pro) and SARS-CoV-2 M(pro) and of rupintrivir in complex with SARS-CoV-2 M(pro) were solved, revealing that all protein residues interacting with the inhibitors are conserved between the two proteins. A detailed analysis of protein-inhibitor interactions indicates that AG7404 has a better fit to the active site of the target protease than rupintrivir. This observation was further confirmed by biochemical FRET assays showing IC(50) values of 47 muM and 101 muM for AG7404 and rupintrivir, respectively, in the case of SARS-CoV-2 M(pro). Equivalent IC(50) values for SARS-CoV-1 also revealed greater inhibitory capacity of AG7404, with a value of 29 muM vs. 66 muM for rupintrivir. Finally, the antiviral activity of the two inhibitors against SARS-CoV-2 was confirmed in a human cell culture model of SARS-CoV-2 infection, although rupintrivir showed a higher potency and selectivity index in this assay. Structure and inhibition of SARS-CoV-1 and SARS-CoV-2 main proteases by oral antiviral compound AG7404.,Fabrega-Ferrer M, Herrera-Morande A, Muriel-Goni S, Perez-Saavedra J, Bueno P, Castro V, Garaigorta U, Gastaminza P, Coll M Antiviral Res. 2022 Dec;208:105458. doi: 10.1016/j.antiviral.2022.105458. Epub , 2022 Nov 3. PMID:36336176[18] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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