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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

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DOI (Published version): 10.1016/j.ejmech.2021.113841

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
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URI: https://cronfa.swan.ac.uk/Record/cronfa57962
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spelling 2021-11-30T15:37:26.9380436 v2 57962 2021-09-20 Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin b97beeed16f8e0524551233ade909565 Marcella Bassetto Marcella Bassetto true false 2021-09-20 FGSEN 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. Journal Article European Journal of Medicinal Chemistry 226 113841 Elsevier BV 0223-5234 Severe inherited blinding diseases, Rhodopsin, Molecular modelling, Small-molecule agents, Synthetic organic chemistry 15 12 2021 2021-12-15 10.1016/j.ejmech.2021.113841 COLLEGE NANME Science and Engineering - Faculty COLLEGE CODE FGSEN Swansea University 2021-11-30T15:37:26.9380436 2021-09-20T09:48:16.2902650 Faculty of Science and Engineering School of Engineering and Applied Sciences - Chemistry Gaia Pasqualetto 1 Elisa Pileggi 2 Martin Schepelmann 3 Carmine Varricchio 4 Malgorzata Rozanowska 5 Andrea Brancale 6 Marcella Bassetto 7 57962__20931__a41addb74ef84e60b33fcaa4ff97153d.pdf Main_Text_final_ACCEPTED.pdf 2021-09-20T09:56:09.4835594 Output 10276088 application/pdf Accepted Manuscript true 2022-09-17T00:00:00.0000000 ©2021 All rights reserved. All article content, except where otherwise noted, is licensed under a Creative Commons Attribution Non-Commercial No Derivatives License (CC-BY-NC-ND) true eng https://creativecommons.org/licenses/by-nc-nd/4.0/
title Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
spellingShingle Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
Marcella Bassetto
title_short Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
title_full Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
title_fullStr Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
title_full_unstemmed Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
title_sort Ligand-based rational design, synthesis and evaluation of novel potential chemical chaperones for opsin
author_id_str_mv b97beeed16f8e0524551233ade909565
author_id_fullname_str_mv b97beeed16f8e0524551233ade909565_***_Marcella Bassetto
author Marcella Bassetto
author2 Gaia Pasqualetto
Elisa Pileggi
Martin Schepelmann
Carmine Varricchio
Malgorzata Rozanowska
Andrea Brancale
Marcella Bassetto
format Journal article
container_title European Journal of Medicinal Chemistry
container_volume 226
container_start_page 113841
publishDate 2021
institution Swansea University
issn 0223-5234
doi_str_mv 10.1016/j.ejmech.2021.113841
publisher Elsevier BV
college_str Faculty of Science and Engineering
hierarchytype
hierarchy_top_id facultyofscienceandengineering
hierarchy_top_title Faculty of Science and Engineering
hierarchy_parent_id facultyofscienceandengineering
hierarchy_parent_title Faculty of Science and Engineering
department_str School of Engineering and Applied Sciences - Chemistry{{{_:::_}}}Faculty of Science and Engineering{{{_:::_}}}School of Engineering and Applied Sciences - Chemistry
document_store_str 1
active_str 0
description 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.
published_date 2021-12-15T04:14:06Z
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