Carnitine is a pharmacological allosteric chaperone of the human lysosomal α -glucosidase - Archive ouverte HAL Access content directly
Journal Articles Journal of Enzyme Inhibition and Medicinal Chemistry Year : 2021

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

Nadia Minopoli
  • Function : Author
Maria Carmina Ferrara
  • Function : Author
Antonietta Tarallo
  • Function : Author
Carla Damiano
  • Function : Author
Caterina Porto
  • Function : Author
Sandra Strollo
  • Function : Author
Gianfranco Peluso
  • Function : Author
Beatrice Cobucci-Ponzano
Giancarlo Parenti
  • Function : Author
Marco Moracci

Abstract

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.

Dates and versions

hal-03400634 , version 1 (25-10-2021)

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Roberta Iacono, Nadia Minopoli, Maria Carmina Ferrara, Antonietta Tarallo, Carla Damiano, et al.. Carnitine is a pharmacological allosteric chaperone of the human lysosomal α -glucosidase. Journal of Enzyme Inhibition and Medicinal Chemistry, 2021, 36 (1), pp.2068-2079. ⟨10.1080/14756366.2021.1975694⟩. ⟨hal-03400634⟩
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