title: Heterocyclic compounds that inhibit Rev-RRE function and human immunodeficiency virus type 1 replication.
abstract: A cell-based screening assay was performed to identify compounds that inhibited the postintegration stage of the human immunodeficiency virus (HIV) life cycle. This assay utilized a cell line that contains the HIV gag and pol genes expressed in a Rev-dependent fashion. The cell line produces about 10 to 15 ng of p24 per milliliter of medium over a 24-h period in the form of viruslike particles. Any compound that inhibits a postintegration step in the HIV life cycle scores in this assay by decreasing particle production. Forty thousand compounds were screened, and 192 compounds were selected from the original screen because they showed more than 50% inhibition at a 10 muM concentration. The cumulative evidence presented in this study strongly suggests that 2 of the 192 compounds work as inhibitors of HIV Rev function. This was determined by a variety of cell-based assays, although the compounds do not interfere with Rev-RRE (Rev response element) binding in vitro. Both compounds inhibit replication of the lab isolate NL4-3 as well as an HIV primary isolate from Brazil (93BR021) and thus are promising leads as therapeutic candidates that target HIV replication through inhibition of Rev function.
authors.affiliation: Department of Microbiology, Myles H Thaler Center for AIDS and Human Retrovirus Research, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Deidra
authors.initials: D
authors.lastname: Shuck-Lee
authors.forename: Fei Fei
authors.initials: FF
authors.lastname: Chen
authors.forename: Ryan
authors.initials: R
authors.lastname: Willard
authors.forename: Sharmila
authors.initials: S
authors.lastname: Raman
authors.forename: Roger
authors.initials: R
authors.lastname: Ptak
authors.forename: Marie-Louise
authors.initials: ML
authors.lastname: Hammarskjold
authors.forename: David
authors.initials: D
authors.lastname: Rekosh
mesh_terms: D000818:Animals; D019380:Anti-HIV Agents / Q000494:pharmacology*; D019556:COS Cells / Q000821:virology; D002460:Cell Line; D002522:Chlorocebus aethiops; D015694:Gene Products, rev / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015752:Genes, env / Q000187:drug effects* / Q000502:physiology; D015658:HIV Infections / Q000821:virology; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006801:Humans; D007963:Leukocytes, Mononuclear / Q000821:virology; D008826:Microbial Sensitivity Tests / Q000379:methods; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D019380:Anti-HIV Agents; D015694:Gene Products, rev; D006571:Heterocyclic Compounds