Ring expanded nucleoside analogues inhibit RNA helicase and intracellular human immunodeficiency virus type 1 replication

J Med Chem. 2008 Aug 28;51(16):5043-51. doi: 10.1021/jm800332m. Epub 2008 Aug 5.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Azepines / chemical synthesis*
  • Azepines / pharmacology*
  • Cell Line
  • DEAD-box RNA Helicases / antagonists & inhibitors*
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology*
  • HIV-1 / drug effects
  • HIV-1 / physiology*
  • Humans
  • Mice
  • Nucleosides / chemical synthesis*
  • Nucleosides / pharmacology*
  • Stereoisomerism
  • Virus Replication / drug effects*

Substances

  • Azepines
  • Enzyme Inhibitors
  • Nucleosides
  • DDX3X protein, human
  • DEAD-box RNA Helicases