5- C-Branched Deoxynojirimycin: Strategy for Designing a 1-Deoxynojirimycin-Based Pharmacological Chaperone with a Nanomolar Affinity for Pompe Disease

  • J Med Chem. 2022 Feb 10;65(3):2329-2341. doi: 10.1021/acs.jmedchem.1c01673.
Atsushi Kato  1 ,  Izumi Nakagome  2 ,  Uta Kanekiyo  1 ,  Tian-Tian Lu  3  4 ,  Yi-Xian Li  3  4 ,  Kosuke Yoshimura  1 ,  Mana Kishida  1 ,  Kenta Shinzawa  1 ,  Tomoki Yoshida  2 ,  Nobutada Tanaka  2 ,  Yue-Mei Jia  3  4 ,  Robert J Nash  5 ,  George W J Fleet  6 ,  Chu-Yi Yu  3  4
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. Beijing National Laboratory for Molecular Science (BNLMS), CAS Key Laboratory of Molecular Recognition and Function, Institute of Chemistry, Chinese Academy of Sciences, Beijing 100190, China.
  • 4. University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5. Institute of Biological, Environmental and Rural Sciences / Phytoquest Limited, Plas Gogerddan, Aberystwyth, Ceredigion SY23 3EB, U.K.
  • 6. Chemistry Research Laboratory, Department of Chemistry, University of Oxford, Oxford OX1 3TA, U.K.
PMID: 35072486 DOI: 10.1021/acs.jmedchem.1c01673
Abstract

In recent years, the function of pharmacological chaperones as a "thermodynamic stabilizer" has been attracting attention in combination therapy. The coadministration of a pharmacological chaperone and recombinant human acid α-glucosidase (rhGAA) leads to improved stability and maturation by binding to the folded state of the rhGAA and thereby promotes enzyme delivery. This study provides the first example of a strategy to design a high-affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5-C-heptyl-DNJ produced a nanomolar affinity for GAA with a Ki value of 0.0047 μM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 μM 5-C-heptyl-DNJ increased the midpoint of the protein denaturation temperature (Tm) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ dose dependency increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease, which may lead to the development of higher-affinity and practically useful chaperones.

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