Bioevaluation of sixteen ADMDP stereoisomers toward alpha-galactosidase A: Development of a new pharmacological chaperone for the treatment of Fabry disease and potential enhancement of enzyme replacement therapy efficiency

  • Eur J Med Chem. 2016 Nov 10:123:14-20. doi: 10.1016/j.ejmech.2016.07.025.
Wei-Chieh Cheng  1 ,  Jen-Hon Wang  2 ,  Huang-Yi Li  3 ,  Sheng-Jhih Lu  3 ,  Jia-Ming Hu  3 ,  Wen-Yi Yun  3 ,  Cheng-Hsin Chiu  3 ,  Wen-Bin Yang  3 ,  Yin-Hsiu Chien  4 ,  Wuh-Liang Hwu  4
Affiliations
  • 1. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, National Cheng-Kung University, 1, University Road, Tainan 701, Taiwan. Electronic address: [email protected].
  • 2. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan; Department of Chemistry, National Cheng-Kung University, 1, University Road, Tainan 701, Taiwan.
  • 3. Genomics Research Center, Academia Sinica, 128, Academia Road, Section 2, Nankang, Taipei 115, Taiwan.
  • 4. Department of Medical Genetics, National Taiwan University Hospital, Taipei, Taiwan.
PMID: 27474919 DOI: 10.1016/j.ejmech.2016.07.025
Abstract

A unique molecular library consisting of all sixteen synthetic ADMDP (1-aminodeoxy-DMDP) stereoisomers has been prepared and evaluated for inhibitory activity against α-Gal A, and ability to impart thermal stabilization of this enzyme. The results of this testing led us to develop a novel pharmacological chaperone for the treatment of Fabry disease. 3-Epimer ADMDP was found to be an effective pharmacological chaperone, able to rescue α-Gal A activity in the lymphoblast of the N215S Fabry patient-derived cell line, without impairment of cellular β-galactosidase activity. When 3-epimer ADMDP was administered with rh-α-Gal A (enzyme replacement therapy) for the treatment of Fabry patient-derived cell lines, improvements in the efficacy of rh-α-Gal A was observed, which suggests this small molecule can also provide clinical benefit of enzyme replacement therapy in Fabry disease.

Keywords
Enzyme replacement therapy; Fabry disease; Lysosomal storage diseases; Lysosomal α-galactosidase A; Pharmacological chaperone; Pyrrolidine-based iminosugar.