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

JOURNAL OF MOLECULAR BIOLOGY

卷:410

Article

Davidson, Amy¹  Begley, Darren W.^1,2  Lau, Carmen¹  Varani, Gabriele^1,3 

[1] Univ Washington, Dept Chem, Seattle, WA 98195 USA

[2] Emerald BioStruct, Bainbridge Isl, WA 98110 USA

[3] Univ Washington, Dept Biochem, Seattle, WA 98195 USA

关键词: HIV;    TAR;    Tat;    RNA;    fragment-based ligand design;   

DOI  :  10.1016/j.jmb.2011.03.039

来源: Elsevier

【 摘 要 】

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. (C) 2011 Elsevier Ltd. All rights reserved.

【 授权许可】

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