2. Academic Validation
  3. Design and Pharmacological Chaperone Effects of N-(4'-Phenylbutyl)-DAB Derivatives Targeting the Lipophilic Pocket of Lysosomal Acid α-Glucosidase

Design and Pharmacological Chaperone Effects of N-(4'-Phenylbutyl)-DAB Derivatives Targeting the Lipophilic Pocket of Lysosomal Acid α-Glucosidase

  • J Med Chem. 2023 Jul 13;66(13):9023-9039. doi: 10.1021/acs.jmedchem.3c00637.
Atsushi Kato 1,  Izumi Nakagome 2,  Maki Kise 1,  Kousuke Yoshimura 1,  Nobutada Tanaka 2,  Robert J Nash 3,  George W J Fleet 4,  Yota Kobayashi 5,  Hayato Ikeda 6,  Takuya Okada 5 6,  Naoki Toyooka 5 6
Affiliations

Affiliations

  • 1 Department of Hospital Pharmacy, University of Toyama, 2630 Sugitani, Toyama 930-0194, Japan.
  • 2 School of Pharmacy, Kitasato University, Tokyo 108-8641, Japan.
  • 3 Institute of Biological, Environmental and Rural Sciences / Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, U.K.
  • 4 Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, U.K.
  • 5 Graduate School of Pharma-Medical Sciences, University of Toyama, Toyama 930-8555, Japan.
  • 6 Faculty of Engineering, University of Toyama, Toyama 930-8555, Japan.
PMID: 37314161 DOI: 10.1021/acs.jmedchem.3c00637
Abstract

This study provides the first example of a strategy to design a practical ligand toward lysosomal acid α-glucosidase (GAA) focusing on N-alkyl derivatives of 1,4-dideoxy-1,4-imino-d-arabinitol (DAB). The optimized N-4'-(p-trifluoromethylphenyl)butyl-DAB (5g) showed a Ki value of 0.73 μM, which was 353-fold higher affinity than N-butyl-DAB (3f) without a terminal phenyl group. Docking analysis showed that the phenyl part of 5g was accommodated in a lipophilic pocket. Furthermore, the p-trifluoromethyl group effectively suppresses the fluctuation of the phenyl group, allowing it to produce a stable bonding form with GAA. 5g increased the midpoint of the protein's protein denaturation temperature (Tm) by 6.6 °C above that in the absence of the ligand and acted as a "thermodynamic stabilizer" to improve the thermal stability of rhGAA. 5g dose-dependently increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation; its effect was comparable to that of DNJ, which is under clinical trials.

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