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Identification of PDE6D as a molecular target of anecortave acetate by transcriptome-wide yeast three-hybrid analysis.

Shepard, Allan and Pang, Iok-Hou and Conrow, Raymond and Rezwan, Mandana and Rutschmann, Katrin and Auerbach, Daniel and SriRamaratnam, Rohitha and Cornish, Virginia (2012) Identification of PDE6D as a molecular target of anecortave acetate by transcriptome-wide yeast three-hybrid analysis. ACS chemical biology. ISSN 1554-8929

Abstract

Glaucoma and age-related macular degeneration are ocular
diseases targeted clinically by anecortave acetate (AA). AA and its deacetylated metabolite, anecortave desacetate (AdesA), are intraocular pressure (IOP)-lowering and angiostatic cortisenes devoid of glucocorti-coid activity but with an unknown mechanism of action. We used a methotrexate-anchored yeast three-hybrid (Y3H) technology to search for binding targets for AA in human trabecular meshwork (TM) cells, the target cell type that controls IOP, a major risk factor in glaucoma. Y3H hits
were filtered by competitive Y3H screens and coimmunoprecipitation experiments and verified by surface plasmon resonance analysis to yield a single target, phosphodiesterase 6-delta (PDE6D). PDE6D is a prenyl- binding protein with additional function outside the PDE6 phototransduction system. Overexpression of PDE6D in mouse eyes caused elevated IOP, and this elevation was reversed by topical ocular application of either AA or AdesA. The identification of PDE6D as the molecular binding partner of AA provides insight into the role of this drug in treating glaucoma.

Item Type: Article
Additional Information: Allan R. Shepard Alcon Research, Ltd., Fort Worth, TX 76134, allan.shepard@alconlabs.com; Telephone 817-615-2312; Fax 817-568-7553 Raymond E. Conrow Alcon Research, Ltd., Fort Worth, TX 76134, ray.conrow@alconlabs.com Mandana Rezwan Dualsystems Biotech AG, Schlieren, Switzerland, rezwan@dualsystems.com Katrin Rutschmann Dualsystems Biotech AG, Schlieren, Switzerland, rutschmann@dualsystems.com Iok-Hou Pang Alcon Research, Ltd., Fort Worth, TX 76134, iok-hou.pang@alconlabs.com Daniel Auerbach Dualsystems Biotech AG, Schlieren, Switzerland, auerbach@dualsystems.com Rohitha SriRamaratnam Department of Chemistry, Columbia University, New York, NY 10027, rs2373@columbia.edu Virginia W. Cornish Department of Chemistry, Columbia University, New York, NY 10027, vc114@columbia.edu; Telephone 212-854-5209; Fax 212-932-1289
Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7060

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