Selective Inhibitors of Human Neuraminidase 3

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.