Chemoenzymatic Synthesis of New Glycopeptide Antibiotics

新型糖肽抗生素的化学酶法合成

• 批准号: 6831755
• 负责人: WEI LU
• 金额: $ 1.7万
• 依托单位: HARVARD MEDICAL SCHOOL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-04 至 2004-12-05
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6831755
• 关键词: alkylation; antibiotics; chimeric proteins; drug design /synthesis /production; drug resistance; drug screening /evaluation; enzyme substrate; glycopeptides; glycosylation; glycosyltransferase; peptide chemical synthesis; postdoctoral investigator; protein engineering; protein purification; site directed mutagenesis; vancomycin

DESCRIPTION (provided by applicant): Chemoenzymatic modifications of the carbohydrate moieties on residue 4 and 6 of glycopeptide have great potential in generating new therapeutics against life-threatening vancomycin-resistant pathogens. However, the studies on the attachment of a variety of sugars at residue 6 of the heptapeptide have not been explored. To facilitate the appendage of various sugars at this position, a teicoplanin enzyme tGtfA will be expressed and purified. Its substrate preference will be studied so that it may be used as a potential catalyst to transfer various carbohydrates to the heptapeptide scaffolds. Moreover, chimeric glycosyltransferase with novel activities will be engineered based on the known structures of glycosyltransferases involved in glycopeptide biosynthesis. In addition, reductive alkylation of two triglycosylated glycopeptides will be carried out not only for discovering new antibiotics but also for improving the efficiency of the chemoenzymatic synthesis of glycopeptide variants.

描述（由申请人提供）： 糖肽残基 4 和 6 上碳水化合物部分的化学酶修饰在产生针对危及生命的万古霉素耐药病原体的新疗法方面具有巨大潜力。然而，尚未探索在七肽残基6处附着多种糖的研究。为了促进各种糖在该位置的附加，将表达并纯化替考拉宁酶 tGtfA。将研究其底物偏好，以便将其用作将各种碳水化合物转移至七肽支架的潜在催化剂。此外，基于参与糖肽生物合成的糖基转移酶的已知结构，将设计具有新活性的嵌合糖基转移酶。此外，对两种三糖基化糖肽进行还原烷基化不仅可以用于发现新的抗生素，还可以提高化学酶法合成糖肽变体的效率。