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G. LaRosa, N. Sharma, R. Miller, S. Min, K. Mudunuri, T. Quach, L. Frye, J. Greenwood, R. Farid, D. Garvey; Discovery of Non-Retinoid Pharmacologic Chaperones for the Treatment of Retinitis Pigmentosa. Invest. Ophthalmol. Vis. Sci. 2009;50(13):2302.
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Identify novel non-retinoid pharmacologic chaperone compounds for the potential treatment of Adult Dominant Retinitis Pigmentosa (ADRP). ADRP is an inherited disorder linked to mutations in the gene that encodes the photoreceptor cell protein opsin. Normally, when bound to its natural substrate, 11-cis retinal, opsin forms the dim-light visual pigment rhodopsin present on photoreceptor rod cells. Many mutations in opsin have been found to be associated with ADRP, and one mutation at opsin codon 23, replacing proline with histidine (P23H), accounts for nearly one-third of ADRP cases of in the US. Some forms of ADRP can be characterized as a Protein Conformational Disease (PCD). Newly synthesized wild-type opsin protein folds properly and is processed through the photoreceptor cell endoplasmic reticulum (ER) and golgi, and transported to the cell surface. Some mutant opsin proteins are misfolded and retained in the ER, forming aggregates, causing ER stress and provoking an Unfolded-Protein Response (UPR). When the ER stress not relieved or adaptive responses are overwhelmed, a pro-apoptotic response can be induced, leading to photoreceptor cell death, and further to retinal degeneration and eventual blindness. Small-molecule based strategies for the treatment of PCDs have been investigated and small-molecules have been found that act as "pharmacological chaperones". These molecules bind and stabilize mutant proteins, allowing their release from the quality control apparatus of the cell, potentially arresting or reversing the cellular degenerative process leading to disease.
Use of rhodopsin crystal structures, molecular modeling, and in silico screening of small molecule compounds, followed by cellular and biochemical assays.
We have identified several series of non-retinoid compounds that act as pharmacologic chaperones for mutant opsin. These molecules bind to mutant opsin and promote the more appropriate processing and transport of these proteins, resulting in increased rhodopsin production and surface expression.
It is possible to identify non-retinoid small molecules that can bind to opsin and act as pharmacologic chaperones. The activities of these molecules in specific in vitro assays and in vivo models will be discussed.
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