Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination
Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms...
| Main Authors: | , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-04-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2022.856804/full |
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| author | Lucile Hoch Lucile Hoch Lucile Hoch Nathalie Bourg Fanny Degrugillier Céline Bruge Céline Bruge Céline Bruge Manon Benabides Manon Benabides Manon Benabides Emilie Pellier Emilie Pellier Emilie Pellier Johana Tournois Johana Tournois Johana Tournois Gurvan Mahé Gurvan Mahé Gurvan Mahé Nicolas Maignan Jack Dawe Maxime Georges David Papazian Nik Subramanian Stéphanie Simon Pascale Fanen Pascale Fanen Cédric Delevoye Cédric Delevoye Isabelle Richard Xavier Nissan Xavier Nissan Xavier Nissan |
| author_facet | Lucile Hoch Lucile Hoch Lucile Hoch Nathalie Bourg Fanny Degrugillier Céline Bruge Céline Bruge Céline Bruge Manon Benabides Manon Benabides Manon Benabides Emilie Pellier Emilie Pellier Emilie Pellier Johana Tournois Johana Tournois Johana Tournois Gurvan Mahé Gurvan Mahé Gurvan Mahé Nicolas Maignan Jack Dawe Maxime Georges David Papazian Nik Subramanian Stéphanie Simon Pascale Fanen Pascale Fanen Cédric Delevoye Cédric Delevoye Isabelle Richard Xavier Nissan Xavier Nissan Xavier Nissan |
| author_sort | Lucile Hoch |
| collection | DOAJ |
| description | Limb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis. |
| first_indexed | 2024-12-10T09:48:24Z |
| format | Article |
| id | doaj.art-2f13ac261f614217a038e04509eca796 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-10T09:48:24Z |
| publishDate | 2022-04-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-2f13ac261f614217a038e04509eca7962022-12-22T01:53:44ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-04-011310.3389/fphar.2022.856804856804Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat CombinationLucile Hoch0Lucile Hoch1Lucile Hoch2Nathalie Bourg3Fanny Degrugillier4Céline Bruge5Céline Bruge6Céline Bruge7Manon Benabides8Manon Benabides9Manon Benabides10Emilie Pellier11Emilie Pellier12Emilie Pellier13Johana Tournois14Johana Tournois15Johana Tournois16Gurvan Mahé17Gurvan Mahé18Gurvan Mahé19Nicolas Maignan20Jack Dawe21Maxime Georges22David Papazian23Nik Subramanian24Stéphanie Simon25Pascale Fanen26Pascale Fanen27Cédric Delevoye28Cédric Delevoye29Isabelle Richard30Xavier Nissan31Xavier Nissan32Xavier Nissan33CECS, I-Stem, Corbeil-Essonne, FranceINSERM U861, I-Stem, Corbeil-Essonne, FranceUEVE U861, I-Stem, Corbeil-Essonne, FranceINTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, Evry, FranceUniversité Paris Est Creteil, INSERM, IMRB, Créteil, FranceCECS, I-Stem, Corbeil-Essonne, FranceINSERM U861, I-Stem, Corbeil-Essonne, FranceUEVE U861, I-Stem, Corbeil-Essonne, FranceCECS, I-Stem, Corbeil-Essonne, FranceINSERM U861, I-Stem, Corbeil-Essonne, FranceUEVE U861, I-Stem, Corbeil-Essonne, FranceCECS, I-Stem, Corbeil-Essonne, FranceINSERM U861, I-Stem, Corbeil-Essonne, FranceUEVE U861, I-Stem, Corbeil-Essonne, FranceCECS, I-Stem, Corbeil-Essonne, FranceINSERM U861, I-Stem, Corbeil-Essonne, FranceUEVE U861, I-Stem, Corbeil-Essonne, FranceCECS, I-Stem, Corbeil-Essonne, FranceINSERM U861, I-Stem, Corbeil-Essonne, FranceUEVE U861, I-Stem, Corbeil-Essonne, FranceKANTIFY, Bruxelles, BelgiumKANTIFY, Bruxelles, BelgiumKANTIFY, Bruxelles, BelgiumKANTIFY, Bruxelles, BelgiumKANTIFY, Bruxelles, BelgiumUniversité Paris Est Creteil, INSERM, IMRB, Créteil, FranceUniversité Paris Est Creteil, INSERM, IMRB, Créteil, FranceDépartement de Genetique, DMU Biologie-Pathologie, GH Mondor-A. Chenevier, AP-HP, Creteil, FranceInstitut Curie, PSL Research University, CNRS, UMR144, Structure and Membrane Compartments, Paris, FranceInstitut Curie, PSL Research University, CNRS, UMR144, Cell and Tissue Imaging Facility (PICT-IBiSA), Paris, FranceINTEGRARE, Genethon, Inserm, Univ Evry, Université Paris-Saclay, Evry, FranceCECS, I-Stem, Corbeil-Essonne, FranceINSERM U861, I-Stem, Corbeil-Essonne, FranceUEVE U861, I-Stem, Corbeil-Essonne, FranceLimb-girdle muscular dystrophy type R3 (LGMD R3) is a rare genetic disorder characterized by a progressive proximal muscle weakness and caused by mutations in the SGCA gene encoding alpha-sarcoglycan (α-SG). Here, we report the results of a mechanistic screening ascertaining the molecular mechanisms involved in the degradation of the most prevalent misfolded R77C-α-SG protein. We performed a combinatorial study to identify drugs potentializing the effect of a low dose of the proteasome inhibitor bortezomib on the R77C-α-SG degradation inhibition. Analysis of the screening associated to artificial intelligence-based predictive ADMET characterization of the hits led to identification of the HDAC inhibitor givinostat as potential therapeutical candidate. Functional characterization revealed that givinostat effect was related to autophagic pathway inhibition, unveiling new theories concerning degradation pathways of misfolded SG proteins. Beyond the identification of a new therapeutic option for LGMD R3 patients, our results shed light on the potential repurposing of givinostat for the treatment of other genetic diseases sharing similar protein degradation defects such as LGMD R5 and cystic fibrosis.https://www.frontiersin.org/articles/10.3389/fphar.2022.856804/fullmisfolded proteindrug repurposinggivinostatHDAC inhibitorautophagy |
| spellingShingle | Lucile Hoch Lucile Hoch Lucile Hoch Nathalie Bourg Fanny Degrugillier Céline Bruge Céline Bruge Céline Bruge Manon Benabides Manon Benabides Manon Benabides Emilie Pellier Emilie Pellier Emilie Pellier Johana Tournois Johana Tournois Johana Tournois Gurvan Mahé Gurvan Mahé Gurvan Mahé Nicolas Maignan Jack Dawe Maxime Georges David Papazian Nik Subramanian Stéphanie Simon Pascale Fanen Pascale Fanen Cédric Delevoye Cédric Delevoye Isabelle Richard Xavier Nissan Xavier Nissan Xavier Nissan Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination Frontiers in Pharmacology misfolded protein drug repurposing givinostat HDAC inhibitor autophagy |
| title | Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination |
| title_full | Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination |
| title_fullStr | Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination |
| title_full_unstemmed | Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination |
| title_short | Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination |
| title_sort | dual blockade of misfolded alpha sarcoglycan degradation by bortezomib and givinostat combination |
| topic | misfolded protein drug repurposing givinostat HDAC inhibitor autophagy |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2022.856804/full |
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