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Crystal Structure of Unlinked NS2B_NS3 Protease from Zika Virus in Complex with Boronate Inhibitor MI-2270
Structural highlights
FunctionPOLG_ZIKV Protein C: Encapsulates the genomic RNA.[UniProtKB:P17763] prM: Acts as a chaperone for envelope protein E during intracellular virion assembly by masking and inactivating envelope protein E fusion peptide. prM is matured in the last step of virion assembly, presumably to avoid catastrophic activation of the viral fusion peptide induced by the acidic pH of the trans-Golgi network. After cleavage by host furin, the pr peptide is released in the extracellular medium and small envelope protein M and envelope protein E homodimers are dissociated.[UniProtKB:P17763] Envelope protein E: Binding to host cell surface receptor is followed by virus internalization through clathrin-mediated endocytosis. Envelope protein E is subsequently involved in membrane fusion between virion and host late endosomes. Synthesized as a homodimer with prM which acts as a chaperone for envelope protein E. After cleavage of prM, envelope protein E dissociate from small envelope protein M and homodimerizes.[UniProtKB:P17763] Non-structural protein 1: Involved in virus replication and regulation of the innate immune response.[UniProtKB:P17763] Non-structural protein 2A: May be involved viral RNA replication and capsid assembly.[UniProtKB:P09732] Non-structural protein 4A: Induces host endoplasmic reticulum membrane rearrangements leading to the formation of virus-induced membranous vesicles hosting the dsRNA and polymerase, functioning as a replication complex. NS4A might also regulate the ATPase activity of the helicase region of Serine protease NS3 chain.[UniProtKB:P17763] Peptide 2k: Functions as a signal peptide for NS4B and is required for the interferon antagonism activity of the latter.[UniProtKB:P17763] Non-structural protein 4B: Inhibits interferon (IFN)-induced host STAT1 phosphorylation and nuclear translocation, thereby preventing the establishment of cellular antiviral state by blocking the IFN-alpha/beta pathway.[UniProtKB:P17763] Publication Abstract from PubMedThe Zika virus (ZIKV) remains a potential threat to the public health due to the lack of both an approved vaccination or a specific treatment. In this work, a series of peptidic inhibitors of the ZIKV protease with boroleucine as P1 residue was synthesized. The highest affinities with K(i) values down to 8 nM were observed for compounds with basic residues in both P2 and P3 position and at the N-terminus. The low potency of reference compounds containing leucine, leucine-amide or isopentylamide as P1 residue suggested a covalent binding mode of the boroleucine-derived inhibitors. This was finally proven by crystal structure determination of the most potent inhibitor from this series in complex with the ZIKV protease. Boroleucine-Derived Covalent Inhibitors of the ZIKV Protease.,Braun NJ, Huber S, Schmacke LC, Heine A, Steinmetzer T ChemMedChem. 2023 Feb 1;18(3):e202200336. doi: 10.1002/cmdc.202200336. Epub 2022 , Nov 21. PMID:36325810[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. References
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