title: Design of Potent Mannose 6-Phosphate Analogues for the Functionalization of Lysosomal Enzymes To Improve the Treatment of Pompe Disease.
abstract: Improving therapeutics delivery in enzyme replacement therapy (ERT) for lysosomal storage disorders is a challenge. Herein, we present the synthesis of novel analogues of mannose 6-phosphate (M6P), known as AMFAs and functionalized at the anomeric position for enzyme grafting. AMFAs are non-phosphate serum-resistant derivatives that efficiently bind the cation-independent mannose 6-phosphate receptor (CI-M6PR), which is the main pathway to address enzymes to lysosomes. One of the AMFAs was used to improve the treatment of the lysosomal myopathy Pompe disease, in which acid α-glucosidase (GAA) is defective. AMFA grafting on a M6P-free recombinant GAA led to a higher uptake of the GAA in adult Pompe fibroblasts in culture as compared to Myozyme, the M6P recombinant GAA. Moreover, the treatment of Pompe adult mice with the AMFA-grafted recombinant enzyme led to a remarkable improvement, even at low doses, in muscle functionality and regeneration, whereas Myozyme had limited efficacy.
authors: NanoMedSyn, 34093, Montpellier cedex 05, France.
authors: Khaled
authors: K
authors: El Cheikh
authors: NanoMedSyn, 34093, Montpellier cedex 05, France.
authors: Ilaria
authors: I
authors: Basile
authors: NanoMedSyn, 34093, Montpellier cedex 05, France.
authors: Afitz
authors: A
authors: Da Silva
authors: CNRS UPS3044, 30380, St Christol-lèz-Alès, France.
authors: Coralie
authors: C
authors: Bernon
authors: CNRS UPS3044, 30380, St Christol-lèz-Alès, France.
authors: Pierre
authors: P
authors: Cérutti
authors: Institut des Biomolécules Max Mousseron, UMR 5247 CNRS UM, Faculté de Pharmacie, 34093, Montpellier cedex 05, France.
authors: Frédéric
authors: F
authors: Salgues
authors: INRA, UMR 1083, 34060, Montpellier, France.
authors: Marc
authors: M
authors: Perez
authors: NanoMedSyn, 34093, Montpellier cedex 05, France.
authors: Marie
authors: M
authors: Maynadier
authors: Institut des Biomolécules Max Mousseron, UMR 5247 CNRS UM, Faculté de Pharmacie, 34093, Montpellier cedex 05, France.
authors: Magali
authors: M
authors: Gary-Bobo
authors: Biochimie Métabolique et Protéique, AH-HP, Hopital Necker Enfants-Malades and Inserm U1151, Institut Necker Enfants Malades, Université Paris-Descartes, Paris, France.
authors: Catherine
authors: C
authors: Caillaud
authors: CNRS UPS3044, 30380, St Christol-lèz-Alès, France.
authors: Martine
authors: M
authors: Cérutti
authors: Institut des Biomolécules Max Mousseron, UMR 5247 CNRS UM, Faculté de Pharmacie, 34093, Montpellier cedex 05, France.
authors: Marcel
authors: M
authors: Garcia
authors: Institut des Biomolécules Max Mousseron, UMR 5247 CNRS UM, Faculté de Pharmacie, 34093, Montpellier cedex 05, France.
authors: Alain
authors: A
authors: Morère
mesh_terms: D000818:Animals; D002236:Carbohydrate Conformation; D015195:Drug Design; D056947:Enzyme Replacement Therapy; D006009:Glycogen Storage Disease Type II / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D008247:Lysosomes / Q000201:enzymology* / Q000378:metabolism; D008360:Mannosephosphates / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D051379:Mice; D000520:alpha-Glucosidases / Q000378:metabolism*
chemical_list: D008360:Mannosephosphates; C027693:mannose-6-phosphate; C509951:GAA protein, human; D000520:alpha-Glucosidases
keywords: acid α-glucosidase; carbohydrates; enzyme replacement therapy; lysosomal storage disease; medicinal chemistry