Givinostat rescues folding of cystathionine beta-synthase and ameliorates murine homocystinuria
DOKPE
- Petrosino, Maria ORCID University of Fribourg
- Zuhra, Karim ORCID University of Fribourg
- Mijatovic, Ela University of Fribourg
- Philipp, Thilo Magnus University of Fribourg
- Bremer, Olivier University of Fribourg
- Ascenção, Kelly ORCID University of Fribourg
- Szabo, Csaba ORCID University of Fribourg
- Majtan, Tomas ORCID University of Fribourg
- 2025
Published in:
- Biochemical Pharmacology. - US: Elsevier BV. - 2025, vol. 239, no. September, p. 1-13
cystathionine beta-synthase
high-throughput screening
protein folding
homocysteine
pharmacological chaperone
English
Homocystinuria (HCU) is an inherited metabolic disorder caused by missense mutations in the cystathionine beta-synthase (CBS) gene, leading to protein misfolding and degradation. Pharmacological chaperones, which stabilize native protein conformations, offer a promising therapeutic strategy, but tools for their identification are lacking. We developed a cell-based CBS folding reporter assay using split-fluorescent protein complementation, focusing on the common HCU-causing CBS I278T variant. In addition to
proteasome inhibitors investigated as potential treatment for HCU, screening of chemical libraries identified several histone deacetylase inhibitors, with givinostat showing the highest recovery of CBS I278T folding and activity. Givinostat binds CBS,
but also acts indirectly by modulating the proteostasis network and protein degradation pathways. Short-term treatment of HCU mice expressing CBS I278T partially restored hepatic CBS expression and reduced serum homocysteine levels. This study presents a novel tool, which lead to identification of new class of potential pharmacological chaperones for HCU, paving the way for personalized assays targeting different pathogenic variants and adaptations for other protein misfolding disorders.
proteasome inhibitors investigated as potential treatment for HCU, screening of chemical libraries identified several histone deacetylase inhibitors, with givinostat showing the highest recovery of CBS I278T folding and activity. Givinostat binds CBS,
but also acts indirectly by modulating the proteostasis network and protein degradation pathways. Short-term treatment of HCU mice expressing CBS I278T partially restored hepatic CBS expression and reduced serum homocysteine levels. This study presents a novel tool, which lead to identification of new class of potential pharmacological chaperones for HCU, paving the way for personalized assays targeting different pathogenic variants and adaptations for other protein misfolding disorders.
- Faculty
- Faculté des sciences et de médecine
- Department
- Médecine 3ème année
- Language
-
- English
- Classification
- Pharmacology, therapeutics, toxicology
- License
- CC BY
- Open access status
- hybrid
- Identifiers
-
- DOI 10.1016/j.bcp.2025.117079
- ISSN 0006-2952
- ISSN 1873-2968
- Persistent URL
- https://folia.unifr.ch/unifr/documents/332254
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