title: A new class of HIV-1 Tat antagonist acting through Tat-TAR inhibition.
abstract: The main transcriptional regulator of the human immunodeficiency virus, the Tat protein, recognizes and binds to a small structured RNA element at the 5' end of every viral mRNA, termed TAR. On the basis of published structural data of the molecular interactions between TAR and Tat-related peptides, we defined requirements for potential low-molecular weight inhibitors of TAR recognition by the Tat protein. In accordance with the resulting concept, a series of compounds was synthesized. In vitro evaluation of their potential to directly interfere with Tat-TAR interaction was used to define a new chemical class of potent Tat antagonistic substances. The most active compound competed with Tat-TAR complexation with a competition dose CD50 of 22 nM in vitro and blocked HIV expression in a cellular Tat transactivation system with an IC50 of 1.2 microM. The close relation between structural features of the interaction between TAR and a new type of inhibitory agent, "In-PRiNts" (for inhibitor of protein-ribonucleotide sequences), such as CGP 40336A and those of the Tat-TAR complex was confirmed by RNase A footprinting and by two-dimensional NMR. Structural implications for the complex between this class of compounds and TAR RNA will be presented.
authors.affiliation: Pharma Research, Novartis Pharma Inc., CH-4002 Basel, Switzerland.
authors.forename: F
authors.initials: F
authors.lastname: Hamy
authors.forename: V
authors.initials: V
authors.lastname: Brondani
authors.forename: A
authors.initials: A
authors.lastname: Flörsheimer
authors.forename: W
authors.initials: W
authors.lastname: Stark
authors.forename: M J
authors.initials: MJ
authors.lastname: Blommers
authors.forename: T
authors.initials: T
authors.lastname: Klimkait
mesh_terms: D000166:Acridines / Q000494:pharmacology*; D019380:Anti-HIV Agents / Q000494:pharmacology*; D001483:Base Sequence; D015195:Drug Design; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015497:HIV-1; D008969:Molecular Sequence Data; D011485:Protein Binding / Q000187:drug effects; D012333:RNA, Messenger / Q000378:metabolism; D012367:RNA, Viral / Q000378:metabolism; D013329:Structure-Activity Relationship; D054322:tat Gene Products, Human Immunodeficiency Virus
chemical_list: D000166:Acridines; D019380:Anti-HIV Agents; D015696:Gene Products, tat; D012333:RNA, Messenger; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus