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Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin / Gaia Pasqualetto, Elisa Pileggi, Martin Schepelmann, Carmine Varricchio, Malgorzata Rozanowska, Andrea Brancale, Marcella Bassetto

European Journal of Medicinal Chemistry, Volume: 226, Start page: 113841

Swansea University Author: Marcella Bassetto

  • Accepted Manuscript under embargo until: 17th September 2022

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 t...

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Published in: European Journal of Medicinal Chemistry
ISSN: 0223-5234
Published: Elsevier BV 2021
Online Access: Check full text

URI: https://cronfa.swan.ac.uk/Record/cronfa57962
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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.
Keywords: Severe inherited blinding diseases, Rhodopsin, Molecular modelling, Small-molecule agents, Synthetic organic chemistry
College: College of Science
Start Page: 113841