Targeting the Chondroitin Sulfate Proteoglycans: Evaluating
Fluorinated Glucosamines and Xylosides in Screens Pertinent to Multiple
Sclerosis
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Posted on 2019-07-24 - 07:14
Chondroitin sulfate
proteoglycans (CSPGs) are upregulated in insults
to the central nervous system, including multiple sclerosis (MS),
an inflammatory demyelinating condition of the central nervous system.
CSPGs appear to be detrimental in MS, as they enhance immune responses
and act as barriers to oligodendrocyte differentiation and thus remyelination.
Despite their deleterious roles, strategies to selectively reduce
CSPG production are lacking. The purpose of this study was to develop,
screen, and describe a series of glucosamine derivatives and xylosides
for their capacity to overcome detrimental CSPGs and inflammatory
processes. Specifically, we assess the ability of analogues to interfere
with CSPG biosynthesis, promote the outgrowth of oligodendrocyte precursor
cells in an inhibitory environment, and lower inflammation by attenuating
the proliferation of T lymphocytes. We highlight the beneficial activities
of a novel compound, per-O-acetylated 4,4-difluoro-N-acetylglucosamine (Ac-4,4-diF-GlcNAc) in vitro,
and report that it reduced inflammation and clinical severity in a
mouse model of MS. Thus, this study represents an important advance,
as we uncover that targeting CSPG biosynthesis with a potent inhibitor
is an effective avenue to ameliorate inflammatory cascades and promote
repair processes in MS and other neurological conditions.
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Stephenson, Erin L.; Zhang, Ping; Ghorbani, Samira; Wang, Aixia; Gu, Jiamin; Keough, Michael B.; et al. (2019). Targeting the Chondroitin Sulfate Proteoglycans: Evaluating
Fluorinated Glucosamines and Xylosides in Screens Pertinent to Multiple
Sclerosis. ACS Publications. Collection. https://doi.org/10.1021/acscentsci.9b00327