Development of Small Molecules with a Noncanonical Binding Mode to HIV-1 Trans Activation Response (TAR) RNA
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- 作者：Fardokht A. Abulwerdi ; Matthew D. Shortridge ; Joanna Sztuba-Solinska ; Robert Wilson ; Stuart F. J. Le Grice ; Gabriele Varani ; John S. Schneekloth Jr.
- 刊名：Journal of Medicinal Chemistry
- 出版年：2016
- 出版时间：December 22, 2016
- 年：2016
- 卷：59
- 期：24
- 页码：11148-11160
- 全文大小：607K
- ISSN：1520-4804
文摘
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.