title: Deciphering structure-activity relationships in a series of Tat/TAR inhibitors.
abstract: A series of pentameric "Polyamide Amino Acids" (PAAs) compounds derived from the same trimeric precursor have been synthesized and investigated as HIV TAR RNA ligands, in the absence and in the presence of a Tat fragment. All PAAs bind TAR with similar sub-micromolar affinities but their ability to compete efficiently with the Tat fragment strongly differs, IC50 ranging from 35 nM to >2 μM. While NMR and CD studies reveal that all PAA interact with TAR at the same site and induce globally the same RNA conformational change upon binding, a comparative thermodynamic study of PAA/TAR equilibria highlights distinct TAR binding modes for Tat competitor and non-competitor PAAs. This led us to suggest two distinct interaction modes that have been further validated by molecular modeling studies. While the binding of Tat competitor PAAs induces a contraction at the TAR bulge region, the binding of non-competitor ones widens it. This could account for the distinct PAA ability to compete with Tat fragment. Our work illustrates how comparative thermodynamic studies of a series of RNA ligands of same chemical family are of value for understanding their binding modes and for rationalizing structure-activity relationships.
authors.affiliation: a Institut de Chimie de Nice UMR7272, Université Nice Sophia Antipolis , 06108 Nice Cedex , France.
authors.forename: Lise
authors.initials: L
authors.lastname: Pascale
authors.affiliation: b Molecular Design Lab, IQS School of Engineering , Universitat Ramon Llull , 08017 Barcelona , Spain.
authors.forename: Alejandro López
authors.initials: AL
authors.lastname: González
authors.affiliation: a Institut de Chimie de Nice UMR7272, Université Nice Sophia Antipolis , 06108 Nice Cedex , France.
authors.forename: Audrey
authors.initials: A
authors.lastname: Di Giorgio
authors.affiliation: a Institut de Chimie de Nice UMR7272, Université Nice Sophia Antipolis , 06108 Nice Cedex , France.
authors.forename: Marc
authors.initials: M
authors.lastname: Gaysinski
authors.affiliation: b Molecular Design Lab, IQS School of Engineering , Universitat Ramon Llull , 08017 Barcelona , Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Teixido Closa
authors.affiliation: b Molecular Design Lab, IQS School of Engineering , Universitat Ramon Llull , 08017 Barcelona , Spain.
authors.forename: Roger Estrada
authors.initials: RE
authors.lastname: Tejedor
authors.affiliation: a Institut de Chimie de Nice UMR7272, Université Nice Sophia Antipolis , 06108 Nice Cedex , France.
authors.forename: Stéphane
authors.initials: S
authors.lastname: Azoulay
authors.affiliation: a Institut de Chimie de Nice UMR7272, Université Nice Sophia Antipolis , 06108 Nice Cedex , France.
authors.forename: Nadia
authors.initials: N
authors.lastname: Patino
mesh_terms: D019380:Anti-HIV Agents / Q000737:chemistry*; D002942:Circular Dichroism; D006801:Humans; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D012367:RNA, Viral / Q000737:chemistry*; D013329:Structure-Activity Relationship; D013816:Thermodynamics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000737:chemistry*
chemical_list: D019380:Anti-HIV Agents; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus
keywords: HIV TAR RNA; RNA ligand interactions; tat inhibitors; thermodynamics