Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA.

ABSTRACT: Small molecules that bind to RNA potently and specifically are relatively rare. The study of molecules that bind to the HIV-1 transactivation response (TAR) hairpin, a cis-acting HIV genomic element, has long been an important model system for the chemistry of targeting RNA. Here we report the synthesis, biochemical, and structural evaluation of a series of molecules that bind to HIV-1 TAR RNA. A promising analogue, 15, retained the TAR binding affinity of the initial hit and displaced a Tat-derived peptide with an IC₅₀ of 40 μM. NMR characterization of a soluble analogue, 2, revealed a noncanonical binding mode for this class of compounds. Finally, evaluation of 2 and 15 by selective 2'-hydroxyl acylation analyzed by primer extension (SHAPE) indicates specificity in binding to

SUBMITTER: Abulwerdi FA 

PROVIDER: S-EPMC5525537 | biostudies-literature | 2016 Dec

REPOSITORIES: biostudies-literature