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


ABSTRACT: 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.

SUBMITTER: Wang D 

PROVIDER: S-EPMC2783946 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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

Wang Deyun D   Iera Jaclyn J   Baker Heather H   Hogan Priscilla P   Ptak Roger R   Yang Lu L   Hartman Tracy T   Buckheit Robert W RW   Desjardins Alexandre A   Yang Ao A   Legault Pascale P   Yedavalli Venkat V   Jeang Kuan-Teh KT   Appella Daniel H DH  

Bioorganic & medicinal chemistry letters 20091023 24


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  ...[more]

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