title: An inhibitor of the Tat/TAR RNA interaction that effectively suppresses HIV-1 replication.
abstract: One of the first steps in HIV gene expression is the recruitment of Tat protein to the transcription machinery after its binding to the RNA response element TAR. Starting from a pool of 3.2 x 10(6) individual chemical entities, we were able to select a hybrid peptoid/peptide oligomer of 9 residues (CGP64222) that was able to block the formation of the Tat/TAR RNA complex in vitro at nanomolar concentrations. NMR studies demonstrated that the compound binds similarly to polypeptides derived from the Tat protein and induces a conformational change in TAR RNA at the Tat-binding site. In addition, 10-30 microM CGP64222 specifically inhibited Tat activity in a cellular Tat-dependent transactivation assay [fusion-induced gene stimulation (FIGS) assay] and blocked HIV-1 replication in primary human lymphocytes. By contrast, peptides of a comparable size and side-chain composition inhibited cell fusion in the FIGS assay and only partially inhibited HIV-1 replication in primary human lymphocytes. Thus, we have discovered a compound, CGP64222, that specifically inhibits the Tat/TAR RNA interaction, both in vitro and in vivo.
authors.affiliation: Novartis, Ltd., Pharmaceuticals, Pharma Research, Basle, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Hamy
authors.forename: E R
authors.initials: ER
authors.lastname: Felder
authors.forename: G
authors.initials: G
authors.lastname: Heizmann
authors.forename: J
authors.initials: J
authors.lastname: Lazdins
authors.forename: F
authors.initials: F
authors.lastname: Aboul-ela
authors.forename: G
authors.initials: G
authors.lastname: Varani
authors.forename: J
authors.initials: J
authors.lastname: Karn
authors.forename: T
authors.initials: T
authors.lastname: Klimkait
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015967:Gene Expression Regulation, Viral; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D019151:Peptide Library; D034444:Peptoids; D011485:Protein Binding / Q000187:drug effects; D012367:RNA, Viral / Q000235:genetics*; D015533:Transcriptional Activation / Q000187:drug effects; D014779:Virus Replication / Q000187:drug effects*; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D019380:Anti-HIV Agents; D015696:Gene Products, tat; D009842:Oligopeptides; D019151:Peptide Library; D034444:Peptoids; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus; C402842:CGP 64222