Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin

Pasqualetto, Gaia, Pileggi, Elisa, Schepelmann, Martin ORCID: https://orcid.org/0000-0002-7017-5426, Varricchio, Carmine ORCID: https://orcid.org/0000-0002-1673-4768, Rozanowska, Malgorzata ORCID: https://orcid.org/0000-0003-2913-8954, Brancale, Andrea ORCID: https://orcid.org/0000-0002-9728-3419 and Bassetto, Marcella ORCID: https://orcid.org/0000-0002-2491-5868 2021. Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin. European Journal of Medicinal Chemistry 226 , 113841. 10.1016/j.ejmech.2021.113841

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Abstract

Inherited blinding diseases retinitis pigmentosa (RP) and a subset of Leber's congenital amaurosis (LCA) are caused by the misfolding and mistrafficking of rhodopsin molecules, which aggregate and accumulate in the endoplasmic reticulum (ER), leading to photoreceptor cell death. One potential therapeutic strategy to prevent the loss of photoreceptors in these conditions is to identify opsin-binding compounds that act as chemical chaperones for opsin, aiding its proper folding and trafficking to the outer cell membrane. Aiming to identify novel compounds with such effect, a rational ligand-based approach was applied to the structure of the visual pigment chromophore, 11-cis-retinal, and its locked analogue 11-cis-6mr-retinal. Following molecular docking studies on the main chromophore binding site of rhodopsin, 49 novel compounds were synthesized according to optimized one-to seven-step synthetic routes. These agents were evaluated for their ability to compete for the chromophore binding site of opsin, and their capacity to increase the trafficking of the P23H opsin mutant from the ER to the cell membrane. Different new molecules displayed an effect in at least one assay, acting either as chemical chaperones or as stabilizers of the 9-cis-retinal-rhodopsin complex. These compounds could provide the basis to develop novel therapeutics for RP and LCA.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Optometry and Vision Sciences Pharmacy
Publisher:	Elsevier
ISSN:	0223-5234
Date of First Compliant Deposit:	22 September 2021
Date of Acceptance:	7 September 2021
Last Modified:	19 Apr 2024 18:09
URI:	https://orca.cardiff.ac.uk/id/eprint/144331

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