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A strategy to develop selective alpha-amylase inhibitors [우수포스터상-생명화학]

2008년 8월 12일 10시 40분 02초
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목 <발표Ⅰ>
저자 및
현순실, 이한재, 유재훈
서울대학교 화학교육과, Korea
Alpha-amylase is one of the most abundant glucosidases that are involved in hydrolysis of carbohydrates. Inhibitors of alpha-amylase from pancreas and saliva have been used to treat diabetics and obesity, respectively. Poor selectivities of the inhibitors, however, cause severe side effects, since the inhibitors failed to differentiate the isoforms in different tissues. It is important to improve the selectivity of inhibitors against different isotypes of enzymes. Most of the inhibitors against alpha-amylase are transition state analogs, which are focused on the recognition part of sugar and the active site such as two glutamate and aspartate. We hypothesize that a combination of sugar substrate and aromatic amino acids could improve selectivities recognizing the extra site beyond the active site of alpha-amylases, which are known to have hydrophobic pockets. Aromatic dipeptide library was constructed and combined with a pentasaccharide substrate. The library was screened against alpha-amylase from human saliva using enzyme kinetics with analytical HPLC technique. Some of these dipeptides have shown to be selective substrates against the enzyme chosen. Then, transition state analogs were incorporated to the chosen peptide instead of hydrolizable substrate unit. The resulting combined inhibitor showed improved affinity and more selectivity relative to known transition state analogs. Furthermore, the strategy from substrate derivatives using aromatic amino acid library could be generally applied to other glucosidase enzymes such as beta-galactodisase.