title: A small-molecule dengue virus entry inhibitor.
abstract: The incidence of dengue fever epidemics has increased dramatically over the last few decades. However, no vaccine or antiviral therapies are available. Therefore, the need for safe and effective antiviral drugs has become imperative. The entry of dengue virus into a host cell is mediated by its major envelope (E) protein. The crystal structure of the E protein reveals a hydrophobic pocket that is presumably important for low-pH-mediated membrane fusion. High-throughput docking with this hydrophobic pocket was performed, and hits were evaluated in cell-based assays. Compound 6 was identified as one of the inhibitors and had an average 50% effective concentration of 119 nM against dengue virus serotype 2 in a human cell line. Mechanism-of-action studies demonstrated that compound 6 acts at an early stage during dengue virus infection. It arrests dengue virus in vesicles that colocalize with endocytosed dextran and inhibits NS3 expression. The inhibitors described in this report can serve as molecular probes for the study of the entry of flavivirus into host cells.
authors.affiliation: Novartis Institute for Tropical Diseases, 10 Biopolis Rd., Chromos Building, Singapore 138670, Singapore. qing_yin.wang@novartis.com
authors.forename: Qing-Yin
authors.initials: QY
authors.lastname: Wang
authors.forename: Sejal J
authors.initials: SJ
authors.lastname: Patel
authors.forename: Eric
authors.initials: E
authors.lastname: Vangrevelinghe
authors.forename: Hao Ying
authors.initials: HY
authors.lastname: Xu
authors.forename: Ranga
authors.initials: R
authors.lastname: Rao
authors.forename: Deana
authors.initials: D
authors.lastname: Jaber
authors.forename: Wouter
authors.initials: W
authors.lastname: Schul
authors.forename: Feng
authors.initials: F
authors.lastname: Gu
authors.forename: Olivier
authors.initials: O
authors.lastname: Heudi
authors.forename: Ngai Ling
authors.initials: NL
authors.lastname: Ma
authors.forename: Mee Kian
authors.initials: MK
authors.lastname: Poh
authors.forename: Wai Yee
authors.initials: WY
authors.lastname: Phong
authors.forename: Thomas H
authors.initials: TH
authors.lastname: Keller
authors.forename: Edgar
authors.initials: E
authors.lastname: Jacoby
authors.forename: Subhash G
authors.initials: SG
authors.lastname: Vasudevan
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002460:Cell Line; D006224:Cricetinae; D003716:Dengue Virus / Q000187:drug effects / Q000254:growth & development / Q000472:pathogenicity*; D006801:Humans; D008958:Models, Molecular; D054852:Small Molecule Libraries; D013329:Structure-Activity Relationship; D014759:Viral Envelope Proteins / Q000037:antagonists & inhibitors; D053586:Virus Internalization / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D054852:Small Molecule Libraries; D014759:Viral Envelope Proteins