Back
Selective Inhibitors of Human Neuraminidase 3.
Journal article

Selective Inhibitors of Human Neuraminidase 3.

  • Guo T Alberta Glycomics Centre and Department of Chemistry , University of Alberta , Edmonton Alberta T6G 2G2 , Canada.
  • Dätwyler P Department of Pharmaceutical Sciences, Pharmacenter , University of Basel , Klingelbergstrasse 50 , CH-4056 Basel , Switzerland.
  • Demina E Division of Medical Genetics, Sainte-Justine University Hospital Research Center , University of Montreal , Montréal , Quebec H3T 1C5 , Canada.
  • Richards MR Alberta Glycomics Centre and Department of Chemistry , University of Alberta , Edmonton Alberta T6G 2G2 , Canada.
  • Ge P Alberta Glycomics Centre and Department of Chemistry , University of Alberta , Edmonton Alberta T6G 2G2 , Canada.
  • Zou C Alberta Glycomics Centre and Department of Chemistry , University of Alberta , Edmonton Alberta T6G 2G2 , Canada.
  • Zheng R Alberta Glycomics Centre and Department of Chemistry , University of Alberta , Edmonton Alberta T6G 2G2 , Canada.
  • Fougerat A Division of Medical Genetics, Sainte-Justine University Hospital Research Center , University of Montreal , Montréal , Quebec H3T 1C5 , Canada.
  • Pshezhetsky AV Division of Medical Genetics, Sainte-Justine University Hospital Research Center , University of Montreal , Montréal , Quebec H3T 1C5 , Canada.
  • Ernst B Department of Pharmaceutical Sciences, Pharmacenter , University of Basel , Klingelbergstrasse 50 , CH-4056 Basel , Switzerland.
  • Cairo CW Alberta Glycomics Centre and Department of Chemistry , University of Alberta , Edmonton Alberta T6G 2G2 , Canada.
Show more…
  • 2018-02-10
Published in:
  • Journal of medicinal chemistry. - 2018
Animals
Enzyme Inhibitors
Humans
Isoenzymes
Mice
N-Acetylneuraminic Acid
Neuraminidase
Small Molecule Libraries
English 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.
Language
  • English
Open access status
closed
Identifiers
Persistent URL
https://sonar.ch/global/documents/231769
Statistics
Document views: 23 File downloads: