2. Academic Validation
  3. Selective Inhibitors of Human Neuraminidase 3

Selective Inhibitors of Human Neuraminidase 3

  • J Med Chem. 2018 Mar 8;61(5):1990-2008. doi: 10.1021/acs.jmedchem.7b01574.
Tianlin Guo 1,  Philipp Dätwyler 2,  Ekaterina Demina 3,  Michele R Richards 1,  Peng Ge 1,  Chunxia Zou 1,  Ruixiang Zheng 1,  Anne Fougerat 3,  Alexey V Pshezhetsky 3,  Beat Ernst 2,  Christopher W Cairo 1
Affiliations

Affiliations

  • 1 Alberta Glycomics Centre and Department of Chemistry , University of Alberta , Edmonton Alberta T6G 2G2 , Canada.
  • 2 Department of Pharmaceutical Sciences, Pharmacenter , University of Basel , Klingelbergstrasse 50 , CH-4056 Basel , Switzerland.
  • 3 Division of Medical Genetics, Sainte-Justine University Hospital Research Center , University of Montreal , Montréal , Quebec H3T 1C5 , Canada.
PMID: 29425031 DOI: 10.1021/acs.jmedchem.7b01574
Abstract

Human neuraminidases (NEU) are associated with human diseases including Cancer, atherosclerosis, and diabetes. To obtain small molecule inhibitors as research tools for the study of their biological functions, we designed a library of 2-deoxy-2,3-didehydro- N-acetylneuraminic acid (DANA) analogues with modifications at C4 and C9 positions. This library allowed us to discover selective inhibitors targeting the human NEU3 isoenzyme. Our most selective inhibitor for NEU3 has a Ki of 320 ± 40 nM and a 15-fold selectivity over Other human neuraminidase isoenzymes. This inhibitor blocks glycolipid processing by NEU3 in vitro. To improve their pharmacokinetic properties, various esters of the best inhibitors were synthesized and evaluated. Finally, we confirmed that our best compounds exhibited selective inhibition of NEU orthologues from murine brain.

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