title: Thermodynamic studies of a series of homologous HIV-1 TAR RNA ligands reveal that loose binders are stronger Tat competitors than tight ones.
abstract: RNA is a major drug target, but the design of small molecules that modulate RNA function remains a great challenge. In this context, a series of structurally homologous 'polyamide amino acids' (PAA) was studied as HIV-1 trans-activating response (TAR) RNA ligands. An extensive thermodynamic study revealed the occurence of an enthalpy-entropy compensation phenomenon resulting in very close TAR affinities for all PAA. However, their binding modes and their ability to compete with the Tat fragment strongly differ according to their structure. Surprisingly, PAA that form loose complexes with TAR were shown to be stronger Tat competitors than those forming tight ones, and thermal denaturation studies demonstrated that loose complexes are more stable than tight ones. This could be correlated to the fact that loose and tight ligands induce distinct RNA conformational changes as revealed by circular dichroism experiments, although nuclear magnetic resonance (NMR) experiments showed that the TAR binding site is the same in all cases. Finally, some loose PAA also display promising inhibitory activities on HIV-infected cells. Altogether, these results lead to a better understanding of RNA interaction modes that could be very useful for devising new ligands of relevant RNA targets.
authors.affiliation: Institut de Chimie de Nice UMR7272, Université de Nice Sophia Antipolis, 06108 Nice Cedex, France.
authors.forename: Lise
authors.initials: L
authors.lastname: Pascale
authors.forename: Stéphane
authors.initials: S
authors.lastname: Azoulay
authors.forename: Audrey
authors.initials: A
authors.lastname: Di Giorgio
authors.forename: Laura
authors.initials: L
authors.lastname: Zenacker
authors.forename: Marc
authors.initials: M
authors.lastname: Gaysinski
authors.forename: Pascal
authors.initials: P
authors.lastname: Clayette
authors.forename: Nadia
authors.initials: N
authors.lastname: Patino
mesh_terms: D000596:Amino Acids / Q000737:chemistry; D019380:Anti-HIV Agents / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001667:Binding, Competitive; D002942:Circular Dichroism; D031541:Fluorescence Resonance Energy Transfer; D016325:HIV Long Terminal Repeat / Q000187:drug effects*; D008024:Ligands; D019906:Nuclear Magnetic Resonance, Biomolecular; D009757:Nylons / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D012367:RNA, Viral / Q000737:chemistry / Q000187:drug effects* / Q000378:metabolism; D013816:Thermodynamics; D054322:tat Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D000596:Amino Acids; D019380:Anti-HIV Agents; D008024:Ligands; D009757:Nylons; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus