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A Small-Molecule Probe Induces a Conformation in HIV TAR RNA Capable of Binding Drug-Like Fragments

Davidson, Amy, Begley, Darren W., Lau, Carmen, Varani, Gabriele
Journal of molecular biology 2011 v.410 no.5 pp. 984-996
Human immunodeficiency virus 1, RNA, drugs, models, nuclear magnetic resonance spectroscopy, screening, transcriptional activation
The HIV-1 transactivation response (TAR) element–Tat interaction is a potentially valuable target for treating HIV infection, but efforts to develop TAR-binding antiviral drugs have not yet yielded a successful candidate for clinical development. In this work, we describe a novel approach toward screening fragments against RNA that uses a chemical probe to target the Tat-binding region of TAR. This probe fulfills two critical roles in the screen: by locking the RNA into a conformation capable of binding other fragments, it simultaneously allows the identification of proximal binding fragments by ligand-based NMR. Using this approach, we have discovered six novel TAR-binding fragments, three of which were docked relative to the probe–RNA structure using experimental NMR restraints. The consistent orientations of functional groups in our data-driven docked structures and common electrostatic properties across all fragment leads reveal a surprising level of selectivity by our fragment-sized screening hits. These models further suggest linking strategies for the development of higher-affinity lead compounds for the inhibition of the TAR–Tat interaction.