Institute of Molecular and Cellular Biosciences, The University of Tokyo, 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
Bioorg Med Chem. 2010 Oct 1;18(19):7022-8. doi: 10.1016/j.bmc.2010.08.014. Epub 2010 Aug 11.
The Retinitis pigmentosa (RP)-causing mutant of rhodopsin, P23H rhodopsin, is folding-defective and unable to traffic beyond the endoplasmic reticulum (ER). This ER retention, and in some cases aggregation, are proposed to result in ER-stress and eventually cell death. The endogenous rhodopsin ligand 11-cis-retinal and its isomer 9-cis-retinal have been shown to act as pharmacological chaperones, promoting proper folding and trafficking of the P23H rhodopsin. In spite of this promising effect, the development of retinals and related polyenealdehydes as pharmacological agents has been hampered by their undesirable properties, which include chemical instability, photolability, and potential retinoidal actions. Here, we report the design and synthesis of a class of more stable nonpolyene-type rhodopsin ligands, structurally distinct from, and with lower toxicity than, retinals. A structure-activity relationship study was conducted using cell-surface expression assay to quantify folding/trafficking efficiency of P23H rhodopsin.
视紫红质（RP）引起的突变，P23H 视紫红质，折叠缺陷，无法运输到内质网（ER）以外。这种 ER 保留，在某些情况下聚集，被认为导致 ER 应激，最终导致细胞死亡。内源性视紫红质配体 11-顺式视黄醛及其异构体 9-顺式视黄醛已被证明具有药理学伴侣的作用，促进 P23H 视紫红质的正确折叠和运输。尽管有这种有希望的效果，但由于其不理想的性质，包括化学不稳定性、光不稳定性和潜在的视黄醛作用，视黄醇和相关聚烯醛作为药理学药物的开发受到了阻碍。在这里，我们报告了一类更稳定的非聚烯型视紫红质配体的设计和合成，它们在结构上与视黄醇不同，毒性也比视黄醇低。使用细胞表面表达测定进行了构效关系研究，以量化 P23H 视紫红质的折叠/运输效率。
