Small-molecule inhibition of HIV pre-mRNA splicing as a novel antiretroviral therapy to overcome drug resistance

PLoS Pathog. 2007 Oct 26;3(10):1530-9. doi: 10.1371/journal.ppat.0030159.

Abstract

The development of multidrug-resistant viruses compromises antiretroviral therapy efficacy and limits therapeutic options. Therefore, it is an ongoing task to identify new targets for antiretroviral therapy and to develop new drugs. Here, we show that an indole derivative (IDC16) that interferes with exonic splicing enhancer activity of the SR protein splicing factor SF2/ASF suppresses the production of key viral proteins, thereby compromising subsequent synthesis of full-length HIV-1 pre-mRNA and assembly of infectious particles. IDC16 inhibits replication of macrophage- and T cell-tropic laboratory strains, clinical isolates, and strains with high-level resistance to inhibitors of viral protease and reverse transcriptase. Importantly, drug treatment of primary blood cells did not alter splicing profiles of endogenous genes involved in cell cycle transition and apoptosis. Thus, human splicing factors represent novel and promising drug targets for the development of antiretroviral therapies, particularly for the inhibition of multidrug-resistant viruses.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Anti-Retroviral Agents / pharmacology*
  • Carbazoles / pharmacology
  • Drug Evaluation, Preclinical
  • Drug Resistance, Viral / genetics*
  • Enzyme-Linked Immunosorbent Assay
  • HIV / drug effects*
  • HIV / genetics
  • Humans
  • Indoles / pharmacology*
  • Isoquinolines / pharmacology*
  • Leukocytes, Mononuclear / virology
  • Macrophages / virology
  • RNA Precursors / drug effects*
  • RNA Splicing / drug effects*
  • RNA, Viral / drug effects
  • Reverse Transcriptase Polymerase Chain Reaction
  • Virus Replication / drug effects

Substances

  • 10-chloro-2,6-dimethyl-2H-pyrido(3',4'-4,5)pyrrolo(2,3-g)isoquinoline
  • Anti-Retroviral Agents
  • Carbazoles
  • Indoles
  • Isoquinolines
  • RNA Precursors
  • RNA, Viral