Inhibition of Fucosyltransferases by GDP- and Sulfone-based Compounds
Date Issued
2009
Date
2009
Author(s)
Chuang, Yu-Ruei
Abstract
Fucosyltransferases (FucTs) catalyze the transfer of L-fucose from GDP-fucose to various glycoconjugate acceptors. Fucosylated glycoconjugates are known to play important roles in numerous physiological and pathological processes, but there are limited studies for FucT inhibition. The development of potent and selective inhibitors for FucTs is thus helpful to understand the relationship between FucTs and their physiological activities and eventually pursue their therapeutic use for drug discovery.GDP, the side product of FucT reactions, is known to exert product inhibition, indicating that GDP has high affinity with FucTs. Our lab synthesized more than 30 various GDP-based derivatives that were investigated in this thesis. By using radio-isotope labeled GDP-fucose, we aimed to study the inhibition of several FucTs, including alpha-1,3-FucT from Helicobacter pylori, and three human FucTs (hFucT2, hFucT6, and hFucT9). Their IC50 and Ki values were obtained. The results indicated that the optimized chain length between GDP and triazole is two carbons, and that triazole and pyrrolidine are indeed better than other aromatic functional groups. Furthermore, additional incorporation of a suitable hydrophobic group was found to enhance the inhibition potency. The analysis of double reciprocal plots indicated that all the GDP-derived inhibitors are competitive inhibitors to the donor substrate (GDP-fucose). Among them, Compound 1 is the best inhibitor of hFucT6 (Ki = 19.9 microM), while 18 is the best for hFucT2 (Ki = 26.7 microM).Moreover, among seventeen sulfones examined for FucT inhibition, S16 was found to be the best for all the four FucTs. Interestingly S16 shows reversible inhibition against HpFucT and hFucT9, while it exhibits irreversible inhibition against hFucT2 and hFucT6. The difference may be due to Michael addition of the vinyl sulfone in the presence of cysteine thiol(s).
Subjects
fucosyltransferase
inhibition
GDP
sulfone
competitive
noncompetitive
uncompetitive
Type
thesis
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