Small-Molecule Inhibitors of Dengue-Virus Entry

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Small-Molecule Inhibitors of Dengue-Virus Entry

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dc.contributor.author Schmidt, Aaron Gregory
dc.contributor.author Lee, Kyungae
dc.contributor.author Yang, Priscilla
dc.contributor.author Harrison, Stephen C.
dc.date.accessioned 2012-12-03T19:55:14Z
dc.date.issued 2012
dc.identifier.citation Schmidt, Aaron G., Kyungae Lee, Priscilla L. Yang, and Stephen C. Harrison. 2012. Small-molecule inhibitors of dengue-virus entry. PLoS Pathogens 8(4): e1002627. en_US
dc.identifier.issn 1553-7366 en_US
dc.identifier.uri http://nrs.harvard.edu/urn-3:HUL.InstRepos:9979956
dc.description.abstract Flavivirus envelope protein (E) mediates membrane fusion and viral entry from endosomes. A low-pH induced, dimer-to-trimer rearrangement and reconfiguration of the membrane-proximal "stem" of the E ectodomain draw together the viral and cellular membranes. We found stem-derived peptides from dengue virus (DV) bind stem-less E trimer and mimic the stem-reconfiguration step in the fusion pathway. We adapted this experiment as a high-throughput screen for small molecules that block peptide binding and thus may inhibit viral entry. A compound identified in this screen, 1662G07, and a number of its analogs reversibly inhibit DV infectivity. They do so by binding the prefusion, dimeric E on the virion surface, before adsorption to a cell. They also block viral fusion with liposomes. Structure-activity relationship studies have led to analogs with submicromolar \(IC_{90} s\) against DV2, and certain analogs are active against DV serotypes 1,2, and 4. The compounds do not inhibit the closely related Kunjin virus. We propose that they bind in a previously identified, E-protein pocket, exposed on the virion surface and although this pocket is closed in the postfusion trimer, its mouth is fully accessible. Examination of the E-trimer coordinates (PDB 1OK8) shows that conformational fluctuations around the hinge could open the pocket without dissociating the trimer or otherwise generating molecular collisions. We propose that compounds such as 1662G07 trap the sE trimer in a "pocket-open" state, which has lost affinity for the stem peptide and cannot support the final "zipping up" of the stem. en_US
dc.language.iso en_US en_US
dc.publisher Public Library of Science en_US
dc.relation.isversionof doi:10.1371/journal.ppat.1002627 en_US
dc.relation.hasversion http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3320583/pdf/ en_US
dash.license LAA
dc.subject biology en_US
dc.subject biochemistry en_US
dc.subject microbiology en_US
dc.subject virology en_US
dc.subject viral structure en_US
dc.subject chemistry en_US
dc.subject medicinal chemistry en_US
dc.title Small-Molecule Inhibitors of Dengue-Virus Entry en_US
dc.type Journal Article en_US
dc.description.version Version of Record en_US
dc.relation.journal PLoS Pathogens en_US
dash.depositing.author Harrison, Stephen C.
dc.date.available 2012-12-03T19:55:14Z

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