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Merged Screening for Human Immunodeficiency Virus Tat and Rev Inhibitors

Novartis Pharma AG, Basel, Switzerland, Aventis Pharma, France

Eduard Felder

Novartis Pharma AG, Basel, Switzerland, Pharmacia Upjohn, Italy

Kenneth Lipson

Novartis Pharma AG, Basel, Switzerland, Sugen, South San Francisco, CA

Thomas Klimkait

Basel Center of HIV Research (BCHR), Institute for Medical Microbiology, University of Basel, Basel, Switzerland

In addition to "conventional" drug discovery targets used in modern strategies, mainly focusing on proteins, recent insights into gene regulation as a novel drug concept have begun to invite the targeting of biomolecular interactions between proteins and RNA. Because two protein-RNA interactions (Tat and trans-activation-responsive element, Rev and Rev-responsive element) are essential for any productive replication of human immunodeficiency virus, this important human pathogen was used as a model system for our studies. The design of a fluorescence-based high throughput assay, in which both targets were presented in the same vessel, enabled us to simultaneously interrogate two characteristics of a potential inhibitor: potency of interference and selectivity toward each of the interactions. Although related systems have been reported for several DNA binders, an extension into interference with transcription events would open a new dimension of cellular regulation. Here we describe the setup of the screening assay for over 110,000 compounds as well as a primary characterization of identified hits. The assay's characteristics demonstrate that a microwell-based dual screening system for RNA binders may add a powerful tool to modern drug discovery.

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