Potential Binding Sites of Pharmacological Chaperone NCGC00241607 on Mutant β-Glucocerebrosidase and Its Efficacy on Patient-Derived Cell Cultures in Gaucher and Parkinson's Disease.

Autor: Kopytova AE; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia.; Department of Molecular Genetic and Nanobiological Technologies, Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg 197022, Russia., Rychkov GN; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia.; Institute of Biomedical Systems and Biotechnology, Peter the Great St.Petersburg Polytechnic University, Saint-Petersburg 195251, Russia., Cheblokov AA; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia., Grigor'eva EV; Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia.; Meshalkin National Medical Research Center, Ministry of Health of the Russian Federation, Novosibirsk 630055, Russia., Nikolaev MA; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia.; Department of Molecular Genetic and Nanobiological Technologies, Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg 197022, Russia., Yarkova ES; Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia., Sorogina DA; Institute of Cytology and Genetics Siberian Branch of Russian Academy of Sciences, Novosibirsk 630090, Russia., Ibatullin FM; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia., Baydakova GV; Research Centre for Medical Genetics, Moscow 115522, Russia., Izyumchenko AD; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia.; Department of Molecular Genetic and Nanobiological Technologies, Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg 197022, Russia., Bogdanova DA; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia., Boitsov VM; Laboratory of Nanobiotechnology, Saint-Petersburg National Research Academic University of the Russian Academy of Sciences, Saint-Petersburg 194021, Russia., Rybakov AV; N.P. Bechtereva Institute of the Human Brain RAS, Saint-Petersburg 197376, Russia., Miliukhina IV; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia.; N.P. Bechtereva Institute of the Human Brain RAS, Saint-Petersburg 197376, Russia., Bezrukikh VA; Almazov National Medical Research Centre, Saint-Petersburg 197341, Russia., Salogub GN; Almazov National Medical Research Centre, Saint-Petersburg 197341, Russia., Zakharova EY; Research Centre for Medical Genetics, Moscow 115522, Russia., Pchelina SN; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia.; Department of Molecular Genetic and Nanobiological Technologies, Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg 197022, Russia., Emelyanov AK; Petersburg Nuclear Physics Institute Named by B.P. Konstantinov of National Research Center «Kurchatov Institute», Gatchina 188300, Russia.; Department of Molecular Genetic and Nanobiological Technologies, Pavlov First Saint-Petersburg State Medical University, Saint-Petersburg 197022, Russia.
Jazyk: angličtina
Zdroj: International journal of molecular sciences [Int J Mol Sci] 2023 May 22; Vol. 24 (10). Date of Electronic Publication: 2023 May 22.
DOI: 10.3390/ijms24109105
Abstrakt: Mutations in the GBA1 gene, encoding the lysosomal enzyme glucocerebrosidase (GCase), cause Gaucher disease (GD) and are the most common genetic risk factor for Parkinson's disease (PD). Pharmacological chaperones (PCs) are being developed as an alternative treatment approach for GD and PD. To date, NCGC00241607 (NCGC607) is one of the most promising PCs. Using molecular docking and molecular dynamics simulation we identified and characterized six allosteric binding sites on the GCase surface suitable for PCs. Two sites were energetically more preferable for NCGC607 and located nearby to the active site of the enzyme. We evaluated the effects of NCGC607 treatment on GCase activity and protein levels, glycolipids concentration in cultured macrophages from GD ( n = 9) and GBA-PD ( n = 5) patients as well as in induced human pluripotent stem cells (iPSC)-derived dopaminergic (DA) neurons from GBA-PD patient. The results showed that NCGC607 treatment increased GCase activity (by 1.3-fold) and protein levels (by 1.5-fold), decreased glycolipids concentration (by 4.0-fold) in cultured macrophages derived from GD patients and also enhanced GCase activity (by 1.5-fold) in cultured macrophages derived from GBA-PD patients with N370S mutation ( p < 0.05). In iPSC-derived DA neurons from GBA-PD patients with N370S mutation NCGC607 treatment increased GCase activity and protein levels by 1.1-fold and 1.7-fold ( p < 0.05). Thus, our results showed that NCGC607 could bind to allosteric sites on the GCase surface and confirmed its efficacy on cultured macrophages from GD and GBA-PD patients as well as on iPSC-derived DA neurons from GBA-PD patients.
Databáze: MEDLINE
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