title: Targeting RNA-protein interactions within the human immunodeficiency virus type 1 lifecycle.
abstract: RNA-protein interactions are vital throughout the HIV-1 life cycle for the successful production of infectious virus particles. One such essential RNA-protein interaction occurs between the full-length genomic viral RNA and the major structural protein of the virus. The initial interaction is between the Gag polyprotein and the viral RNA packaging signal (psi or Ψ), a highly conserved RNA structural element within the 5'-UTR of the HIV-1 genome, which has gained attention as a potential therapeutic target. Here, we report the application of a target-based assay to identify small molecules, which modulate the interaction between Gag and Ψ. We then demonstrate that one such molecule exhibits potent inhibitory activity in a viral replication assay. The mode of binding of the lead molecules to the RNA target was characterized by ¹H NMR spectroscopy.
authors.affiliation: Department of Chemistry, University of Cambridge , Lensfield Road, Cambridge, CB2 1EW, U.K.
authors.forename: Neil M
authors.initials: NM
authors.lastname: Bell
authors.forename: Anne
authors.initials: A
authors.lastname: L'Hernault
authors.forename: Pierre
authors.initials: P
authors.lastname: Murat
authors.forename: James E
authors.initials: JE
authors.lastname: Richards
authors.forename: Andrew M L
authors.initials: AM
authors.lastname: Lever
authors.forename: Shankar
authors.initials: S
authors.lastname: Balasubramanian
mesh_terms: D019380:Anti-HIV Agents / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology*; D001665:Binding Sites; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D057809:HEK293 Cells; D015658:HIV Infections / Q000188:drug therapy; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy; D009690:Nucleic Acid Conformation / Q000187:drug effects; D009691:Nucleic Acid Denaturation / Q000187:drug effects; D009994:Osmolar Concentration; D011806:Quinolinium Compounds / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D020038:RNA, Spliced Leader / Q000187:drug effects*; D012367:RNA, Viral / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012261:Ribonucleoproteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D012545:Schiff Bases / Q000009:adverse effects / Q000737:chemistry / Q000494:pharmacology; D054852:Small Molecule Libraries; D014779:Virus Replication / Q000187:drug effects*; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000037:antagonists & inhibitors* / Q000378:metabolism
chemical_list: D019380:Anti-HIV Agents; C586750:NSC-260594; D011806:Quinolinium Compounds; D020038:RNA, Spliced Leader; D012367:RNA, Viral; D012261:Ribonucleoproteins; D012545:Schiff Bases; D054852:Small Molecule Libraries; D054301:gag Gene Products, Human Immunodeficiency Virus