Enzymes are proteins that catalyze metabolism and biosynthesis in living systems and are important targets for drug discovery. For instance, the famous neuraminidase inhibitor, Tamiflu, has been prescribed to treat the infection of influenza virus.
Researchers in Taiwan have developed a novel way of finding extremely potent enzyme inhibitors. The picomolar inhibitors discovered in this study against fucosidase represents the most powerful glycosidase inhibitor known to date. Fucosidase is an enzyme to catalyze the hydrolytic removal of fucose residues and plays essential roles in several diseases, including inflammation, cancer and cystic fibrosis. The method paves the way for drug discovery in a rapid and high-throughput manner.
The research team was headed by Drs. Chun-Hung Lin and Chi-Huey Wong at the Institute of Biological Chemistry and Genomics Research Center, Academia Sinica. This team used an iminocyclitol as a core to mimic the transition state of fucosidase reaction, and then incorporated an additional group to the core using this strategy to rapidly identify most potent inhibitors. The rapid diversity-oriented synthesis was carried out in microtiter plates followed by enzyme activity assay in situ without protecting group manipulation and purification. Therefore, the screening was conducted with minimized cost.
“The synthesis and screening of one thousand compounds, for example, can be finished within a couple of hours or days, in a sharp contrast to traditional work that takes several months or even more than a year” mentioned by Prof. Wong. The resulting inhibitors were highly specific and showed limited or no inhibition against similar enzymes. Furthermore, this method can be used to detect irreversible inhibition that could ultimately enhance the enzyme affinity up to several hundred folds by means of conformational change.
The research team at Academia Sinica has developed at least five reactions to be used in this manner for drug discovery. The research breakthrough was published in Angewandte Chem Int Ed (2003, 42, 4661-4664) and Chemistry and Biology (2004, 11, 1301-1306).