Identification
of Selective Inhibitors for Human Neuraminidase
Isoenzymes Using C4,C7-Modified 2‑Deoxy-2,3-didehydro‑<i>N</i>‑acetylneuraminic Acid (DANA) Analogues
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Abstract
In
the past two decades, human neuraminidases (human sialidases,
hNEUs) have been found to be involved in numerous pathways in biology.
The development of selective and potent inhibitors of these enzymes
will provide critical tools for glycobiology, help to avoid undesired
side effects of antivirals, and may reveal new small-molecule therapeutic
targets for human cancers. However, because of the high active site
homology of the hNEU isoenzymes, little progress in the design and
synthesis of selective inhibitors has been realized. Guided by our
previous studies of human NEU3 inhibitors, we designed a series of
C4,C7-modified analogues of 2-deoxy-2,3-didehydro-<i>N</i>-acetylneuraminic acid (DANA) and tested them against the full panel
of hNEU isoenzymes (NEU1, NEU2, NEU3, NEU4). We identified inhibitors
with up to 38-fold selectivity for NEU3 and 12-fold selectivity for
NEU2 over all other isoenzymes. We also identified compounds that
targeted NEU2 and NEU3 with similar potency