[Structural development study of a novel pharmacological chaperone for folding-defective rhodopsin mutants...

The retinitis pigmentosa (RP)-causing mutant of rhodopsin, Pro23His (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.