title: Ring expanded nucleoside analogues inhibit RNA helicase and intracellular human immunodeficiency virus type 1 replication.
abstract: A series of ring expanded nucleoside (REN) analogues were synthesized and screened for inhibition of cellular RNA helicase activity and human immunodeficiency virus type 1 (HIV-1) replication. We identified two compounds, 1 and 2, that inhibited the ATP dependent activity of human RNA helicase DDX3. Compounds 1 and 2 also suppressed HIV-1 replication in T cells and monocyte-derived macrophages. Neither compound at therapeutic doses was significantly toxic in ex vivo cell culture or in vivo in mice. Our findings provide proof-of-concept that a cellular factor, an RNA helicase, could be targeted for inhibiting HIV-1 replication.
authors.affiliation: Molecular Virology Section, Laboratory of Molecular Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland 20892, USA.
authors.forename: Venkat S R K
authors.initials: VS
authors.lastname: Yedavalli
authors.forename: Ning
authors.initials: N
authors.lastname: Zhang
authors.forename: Hongyi
authors.initials: H
authors.lastname: Cai
authors.forename: Peng
authors.initials: P
authors.lastname: Zhang
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Starost
authors.forename: Ramachandra S
authors.initials: RS
authors.lastname: Hosmane
authors.forename: Kuan-Teh
authors.initials: KT
authors.lastname: Jeang
mesh_terms: D000818:Animals; D001381:Azepines / Q000138:chemical synthesis* / Q000494:pharmacology*; D002460:Cell Line; D053487:DEAD-box RNA Helicases / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D051379:Mice; D009705:Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology*; D013237:Stereoisomerism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D001381:Azepines; D004791:Enzyme Inhibitors; D009705:Nucleosides; C119332:DDX3X protein, human; D053487:DEAD-box RNA Helicases