title: Novel benzoxazole inhibitor of dengue virus replication that targets the NS3 helicase.
abstract: Dengue virus (DENV) is the predominant mosquito-borne viral pathogen that infects humans with an estimated 50 to 100 million infections per year worldwide. Over the past 50 years, the incidence of dengue disease has increased dramatically and the virus is now endemic in more than 100 countries. Moreover, multiple serotypes of DENV are now found in the same geographic region, increasing the likelihood of more severe forms of disease. Despite extensive research, there are still no approved vaccines or therapeutics commercially available to treat DENV infection. Here we report the results of a high-throughput screen of a chemical compound library using a whole-virus assay that identified a novel small-molecule inhibitor of DENV, ST-610, that potently and selectively inhibits all four serotypes of DENV replication in vitro. Sequence analysis of drug-resistant virus isolates has identified a single point mutation, A263T, in the NS3 helicase domain that confers resistance to this compound. ST-610 inhibits DENV NS3 helicase RNA unwinding activity in a molecular-beacon-based helicase assay but does not inhibit nucleoside triphosphatase activity based on a malachite green ATPase assay. ST-610 is nonmutagenic, is well tolerated (nontoxic) in mice, and has shown efficacy in a sublethal murine model of DENV infection with the ability to significantly reduce viremia and viral load compared to vehicle controls.
authors: SIGA Technologies, Inc, Corvallis, Oregon, USA. cbyrd@siga.com
authors: Chelsea M
authors: CM
authors: Byrd
authors: Douglas W
authors: DW
authors: Grosenbach
authors: Aklile
authors: A
authors: Berhanu
authors: Dongcheng
authors: D
authors: Dai
authors: Kevin F
authors: KF
authors: Jones
authors: Kara B
authors: KB
authors: Cardwell
authors: Christine
authors: C
authors: Schneider
authors: Guang
authors: G
authors: Yang
authors: Shanthakumar
authors: S
authors: Tyavanagimatt
authors: Chris
authors: C
authors: Harver
authors: Kristin A
authors: KA
authors: Wineinger
authors: Jessica
authors: J
authors: Page
authors: Eric
authors: E
authors: Stavale
authors: Melialani A
authors: MA
authors: Stone
authors: Kathleen P
authors: KP
authors: Fuller
authors: Candace
authors: C
authors: Lovejoy
authors: Janet M
authors: JM
authors: Leeds
authors: Dennis E
authors: DE
authors: Hruby
authors: Robert
authors: R
authors: Jordan
mesh_terms: D000818:Animals; D001583:Benzoxazoles / Q000627:therapeutic use*; D002460:Cell Line; D003715:Dengue / Q000188:drug therapy*; D003716:Dengue Virus / Q000187:drug effects* / Q000201:enzymology* / Q000235:genetics / Q000472:pathogenicity; D004285:Dogs; D024882:Drug Resistance, Viral / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D020365:RNA Helicases / Q000037:antagonists & inhibitors* / Q000235:genetics; D014709:Vero Cells; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D001583:Benzoxazoles; D017361:Viral Nonstructural Proteins; D020365:RNA Helicases
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