Multivalent binding oligomers inhibit HIV Tat-TAR interaction critical for viral replication

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:19

Article

Wang, Deyun¹  Iera, Jaclyn¹  Baker, Heather¹  Hogan, Priscilla²  Ptak, Roger²  Yang, Lu³  Hartman, Tracy³  Buckheit, Robert W., Jr.³  Desjardins, Alexandre⁴  Yang, Ao⁴  Legault, Pascale⁴  Yedavalli, Venkat⁵  Jeang, Kuan-Teh⁵  Appella, Daniel H.¹ 

[1] NIDDK, Bioorgan Chem Lab, NIH, DHHS, Bethesda, MD 20892 USA

[2] So Res Inst, Frederick, MD 21701 USA

[3] ImQuest Biosci Inc, Frederick, MD 21704 USA

[4] Univ Montreal, Dept Biochim, Montreal, PQ H3C 3J7, Canada

[5] NIAID, Mol Virol Sect, NIH, DHHS, Bethesda, MD 20892 USA

关键词: HIV;    RNA;    TAR;    Multivalency;   

DOI  :  10.1016/j.bmcl.2009.10.078

来源: Elsevier

【 摘 要 】

We describe the development of a new type of scaffold to target RNA structures. Multivalent binding oligomers (MBOs) are molecules in which multiple sidechains extend from a polyamine backbone such that favorable RNA binding occurs. We have used this strategy to develop MBO-based inhibitors to prevent the association of a protein-RNA complex, Tat-TAR, that is essential for HIV replication. In vitro binding assays combined with model cell-based assays demonstrate that the optimal MBOs inhibit Tat-TAR binding at low micromolar concentrations. Antiviral studies are also consistent with the in vitro and cell-based assays. MBOs provide a framework for the development of future RNA-targeting molecules. Published by Elsevier Ltd.

【 授权许可】

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