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

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 TAR within the context of an in vitro-synthesized 365-nt
HIV-1 5′-untranslated region (UTR). Thus, these compounds exhibit
a novel and specific mode of interaction with TAR, providing important
suggestions for RNA ligand design.