Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination - Approches génétiques intégrées et nouvelles thérapies pour les maladies rares Accéder directement au contenu
Article Dans Une Revue Frontiers in Pharmacology Année : 2022

Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination

Nicolas Maignan
  • Fonction : Auteur
Jack Dawe
  • Fonction : Auteur
Maxime Georges
  • Fonction : Auteur
David Papazian
  • Fonction : Auteur
Nik Subramanian
  • Fonction : Auteur

Résumé

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.
Fichier principal
Vignette du fichier
2022_Hoch_Front Pharmacol.pdf (4.23 Mo) Télécharger le fichier
Origine : Fichiers éditeurs autorisés sur une archive ouverte

Dates et versions

hal-03874719 , version 1 (28-11-2022)

Identifiants

Citer

Lucile Hoch, Nathalie Bourg, Fanny Degrugillier, Céline Bruge, Manon Benabides, et al.. Dual Blockade of Misfolded Alpha-Sarcoglycan Degradation by Bortezomib and Givinostat Combination. Frontiers in Pharmacology, 2022, 13, ⟨10.3389/fphar.2022.856804⟩. ⟨hal-03874719⟩
26 Consultations
20 Téléchargements

Altmetric

Partager

Gmail Facebook X LinkedIn More