Carnitine is a pharmacological allosteric chaperone of the human lysosomal α-glucosidase

Autor: Roberta Iacono, Nadia Minopoli, Maria Carmina Ferrara, Antonietta Tarallo, Carla Damiano, Caterina Porto, Sandra Strollo, Véronique Roig-Zamboni, Gianfranco Peluso, Gerlind Sulzenbacher, Beatrice Cobucci-Ponzano, Giancarlo Parenti, Marco Moracci
Jazyk: angličtina
Rok vydání: 2021
Předmět:
Zdroj: Journal of Enzyme Inhibition and Medicinal Chemistry, Vol 36, Iss 1, Pp 2068-2079 (2021)
Druh dokumentu: article
ISSN: 1475-6366
1475-6374
14756366
DOI: 10.1080/14756366.2021.1975694
Popis: Pompe disease is an inherited metabolic disorder due to the deficiency of the lysosomal acid α-glucosidase (GAA). The only approved treatment is enzyme replacement therapy with the recombinant enzyme (rhGAA). Further approaches like pharmacological chaperone therapy, based on the stabilising effect induced by small molecules on the target enzyme, could be a promising strategy. However, most known chaperones could be limited by their potential inhibitory effects on patient’s enzymes. Here we report on the discovery of novel chaperones for rhGAA, L- and D-carnitine, and the related compound acetyl-D-carnitine. These drugs stabilise the enzyme at pH and temperature without inhibiting the activity and acted synergistically with active-site directed pharmacological chaperones. Remarkably, they enhanced by 4-fold the acid α-glucosidase activity in fibroblasts from three Pompe patients with added rhGAA. This synergistic effect of L-carnitine and rhGAA has the potential to be translated into improved therapeutic efficacy of ERT in Pompe disease.
Databáze: Directory of Open Access Journals
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje