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Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins

Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these condit...

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Autores principales: Pasqualetto, Gaia, Schepelmann, Martin, Varricchio, Carmine, Pileggi, Elisa, Khogali, Caroline, Morgan, Siân R., Boostrom, Ian, Rozanowska, Malgorzata, Brancale, Andrea, Ferla, Salvatore, Bassetto, Marcella
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660337/
https://www.ncbi.nlm.nih.gov/pubmed/33114011
http://dx.doi.org/10.3390/molecules25214904
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author Pasqualetto, Gaia
Schepelmann, Martin
Varricchio, Carmine
Pileggi, Elisa
Khogali, Caroline
Morgan, Siân R.
Boostrom, Ian
Rozanowska, Malgorzata
Brancale, Andrea
Ferla, Salvatore
Bassetto, Marcella
author_facet Pasqualetto, Gaia
Schepelmann, Martin
Varricchio, Carmine
Pileggi, Elisa
Khogali, Caroline
Morgan, Siân R.
Boostrom, Ian
Rozanowska, Malgorzata
Brancale, Andrea
Ferla, Salvatore
Bassetto, Marcella
author_sort Pasqualetto, Gaia
collection PubMed
description Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these conditions is to use opsin-binding compounds as chemical chaperones for opsin. Such molecules have previously shown the ability to aid rhodopsin folding and proper trafficking to the outer cell membranes of photoreceptors. As means to identify novel chemical chaperones for rhodopsin, a structure-based virtual screening of commercially available drug-like compounds (300,000) was performed on the main binding site of the visual pigment chromophore, the 11-cis-retinal. The best 24 virtual hits were examined for their ability to compete for the chromophore-binding site of opsin. Among these, four small molecules demonstrated the ability to reduce the rate constant for the formation of the 9-cis-retinal-rhodopsin complex, while five molecules surprisingly enhanced the formation of this complex. Compound 7, 13, 20 and 23 showed a weak but detectable increase in the trafficking of the P23H mutant, widely used as a model for both retinitis pigmentosa and Leber’s congenital amaurosis, from the ER to the cell membrane. The compounds did not show any relevant cytotoxicity in two different human cell lines, with the only exception of 13. Based on the structures of these active compounds, a series of in silico studies gave important insights on the potential structural features required for a molecule to act either as chemical chaperone or as stabiliser of the 11-cis-retinal-rhodopsin complex. Thus, this study revealed a series of small molecules that represent a solid foundation for the future development of novel therapeutics against these severe inherited blinding diseases.
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spelling pubmed-76603372020-11-13 Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins Pasqualetto, Gaia Schepelmann, Martin Varricchio, Carmine Pileggi, Elisa Khogali, Caroline Morgan, Siân R. Boostrom, Ian Rozanowska, Malgorzata Brancale, Andrea Ferla, Salvatore Bassetto, Marcella Molecules Article Accumulation of misfolded and mistrafficked rhodopsin on the endoplasmic reticulum of photoreceptor cells has a pivotal role in the pathogenesis of retinitis pigmentosa and a subset of Leber’s congenital amaurosis. One potential strategy to reduce rhodopsin misfolding and aggregation in these conditions is to use opsin-binding compounds as chemical chaperones for opsin. Such molecules have previously shown the ability to aid rhodopsin folding and proper trafficking to the outer cell membranes of photoreceptors. As means to identify novel chemical chaperones for rhodopsin, a structure-based virtual screening of commercially available drug-like compounds (300,000) was performed on the main binding site of the visual pigment chromophore, the 11-cis-retinal. The best 24 virtual hits were examined for their ability to compete for the chromophore-binding site of opsin. Among these, four small molecules demonstrated the ability to reduce the rate constant for the formation of the 9-cis-retinal-rhodopsin complex, while five molecules surprisingly enhanced the formation of this complex. Compound 7, 13, 20 and 23 showed a weak but detectable increase in the trafficking of the P23H mutant, widely used as a model for both retinitis pigmentosa and Leber’s congenital amaurosis, from the ER to the cell membrane. The compounds did not show any relevant cytotoxicity in two different human cell lines, with the only exception of 13. Based on the structures of these active compounds, a series of in silico studies gave important insights on the potential structural features required for a molecule to act either as chemical chaperone or as stabiliser of the 11-cis-retinal-rhodopsin complex. Thus, this study revealed a series of small molecules that represent a solid foundation for the future development of novel therapeutics against these severe inherited blinding diseases. MDPI 2020-10-23 /pmc/articles/PMC7660337/ /pubmed/33114011 http://dx.doi.org/10.3390/molecules25214904 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pasqualetto, Gaia
Schepelmann, Martin
Varricchio, Carmine
Pileggi, Elisa
Khogali, Caroline
Morgan, Siân R.
Boostrom, Ian
Rozanowska, Malgorzata
Brancale, Andrea
Ferla, Salvatore
Bassetto, Marcella
Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins
title Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins
title_full Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins
title_fullStr Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins
title_full_unstemmed Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins
title_short Computational Studies towards the Identification of Novel Rhodopsin-Binding Compounds as Chemical Chaperones for Misfolded Opsins
title_sort computational studies towards the identification of novel rhodopsin-binding compounds as chemical chaperones for misfolded opsins
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7660337/
https://www.ncbi.nlm.nih.gov/pubmed/33114011
http://dx.doi.org/10.3390/molecules25214904
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