Allosteric quinoxaline-based inhibitors of the flavivirus NS2B/NS3 protease
Rao, Desaboini Nageswara
Shaqra, Ala M
Nalivaika, Ellen A
Kurt Yilmaz, Nese
Schiffer, Celia A
Document TypeJournal Article
MetadataShow full item record
AbstractViruses from the Flavivirus genus infect millions of people worldwide and cause severe diseases, including recent epidemics of dengue virus (DENV), and Zika virus (ZIKV). There is currently no antiviral treatment against flavivirus infections, despite considerable efforts to develop inhibitors against essential viral enzymes including NS2B/NS3 protease. Targeting the flavivirus NS2B/NS3 protease proved to be challenging because of the conformational dynamics, topology, and electrostatic properties of the active site. Here, we report the identification of quinoxaline-based allosteric inhibitors by fragment-based drug discovery approach as a promising new drug-like scaffold to target the NS2B/NS3 protease. Enzymatic assays and mutational analysis of the allosteric site in ZIKV NS2B/NS3 protease support noncompetitive inhibition mechanism as well as engineered DENV protease construct indicating the compounds likely compete with the NS2B cofactor for binding to the protease domain. Furthermore, antiviral activity confirmed the therapeutic potential of this new inhibitor scaffold.
SourceZephyr J, Rao DN, Johnson C, Shaqra AM, Nalivaika EA, Jordan A, Kurt Yilmaz N, Ali A, Schiffer CA. Allosteric quinoxaline-based inhibitors of the flavivirus NS2B/NS3 protease. Bioorg Chem. 2023 Feb;131:106269. doi: 10.1016/j.bioorg.2022.106269. Epub 2022 Nov 19. PMID: 36446201.
Permanent Link to this Itemhttp://hdl.handle.net/20.500.14038/51573
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