Identification of potential pharmacological chaperones that selectively stabilize mutated Aspartoacylases in Canavan disease.

Autor: Poddar NK; Department of Biosciences, Manipal University Jaipur, Jaipur-Ajmer Express Highway, Dehmi Kalan, Near GVK Toll Plaza, Jaipur, Rajasthan 303007, India; Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA. Electronic address: niteshkumar.poddar@jaipur.manipal.edu., Wijayasinghe YS; Department of Biochemistry and Molecular Biology, Indiana University School of Medicine, Indianapolis, IN 46202, USA; Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA., Viola RE; Department of Chemistry and Biochemistry, The University of Toledo, Toledo, OH 43606, USA.
Jazyk: angličtina
Zdroj: Biochimica et biophysica acta. Proteins and proteomics [Biochim Biophys Acta Proteins Proteom] 2024 Nov 01; Vol. 1872 (6), pp. 141043. Date of Electronic Publication: 2024 Aug 09.
DOI: 10.1016/j.bbapap.2024.141043
Abstrakt: Canavan disease is caused by mutations in the ASPA gene, leading to diminished catalytic activity of aspartoacylase in the brain. Clinical missense mutations are found throughout the enzyme structure, with many of these mutated enzymes having not only decreased activity but also compromised stability. High-throughput screening of a small molecule library has identified several compounds that significantly increase the thermal stability of the E285A mutant enzyme, the most predominant clinical mutation in Canavan disease, while having a negligible effect on the native enzyme. Based on the initial successes, some structural analogs of these initial hits were selected for further examination. Glutathione, NAAG and patulin were each confirmed to be competitive inhibitors, indicating the binding of these compounds at the dimer interface or near the active site of the E285A enzyme. The experimental results were theoretically examined with the help of the docking analysis method. The structure activity-guided optimization of these compounds can potentially lead to potential pharmacological chaperones that could alleviate the detrimental effect of ASPA mutations in Canavan patients.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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