jm8b01411_si_002.csv (5.14 kB)
Selective Inhibitors of Human Neuraminidase 1 (NEU1)
dataset
posted on 2018-11-20, 00:00 authored by Tianlin Guo, Rachel Héon-Roberts, Chunxia Zou, Ruixiang Zheng, Alexey V. Pshezhetsky, Christopher W. CairoInhibitors
of human neuraminidase enzymes (NEU) are recognized
as important tools for the study of the biological functions of NEU
and will be potent tools for elucidating the role of these enzymes
in regulating the repertoire of cellular glycans. Here we report the
discovery of selective inhibitors of the human neuraminidase 1 (NEU1)
and neuraminidase 2 (NEU2) enzymes with exceptional potency. A library
of modified 2-deoxy-2,3-didehydro-N-acetylneuraminic
acid (DANA) analogues, with variability in the C5- or C9-position,
were synthesized and evaluated against four human neuraminidase isoenyzmes
(NEU1–4). Hydrophobic groups with an amide linker at the C5
and C9 positions were well accommodated by NEU1, and a hexanamido
group was found to give the best potency at both positions. While
the C5-hexanamido-C9-hexanamido-DANA analogue did not show synergistic
improvements for combined modification, an extended alkylamide at
an individual position combined with a smaller group at the second
gave increased potency. The best NEU1 inhibitor identified was a C5-hexanamido-C9-acetamido-DANA
that had a Ki of 53 ± 5 nM and 340-fold
selectivity over other isoenzymes. Additionally, we demonstrated that
C5-modifications combined with a C4-guandino group provided the most
potent NEU2 inhibitor reported, with a Ki of 1.3 ± 0.2 μM and 7-fold selectivity over other NEU
isoenzymes.