Semisynthesis of N-glycoprotein libraries

N-糖蛋白文库的半合成

• 批准号: 220916279
• 负责人: Professor Dr. Carlo Unverzagt
• 金额: --
• 依托单位: Arbeitsgruppe Bioorganische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 财政年份: 2012
• 资助国家: 德国
• 起止时间: 2011-12-31 至 2021-12-31
• 项目状态: 已结题
• 来源: https://gepris.dfg.de/gepris/projekt/220916279?language=en
• 关键词: Semisynthesis; glycoprotein; libraries

The function of glycoproteins is frequently regulated by their carbohydrate moieties. These sugar moieties show a natural microheterogeneity. The consequences of microheterogeneity are not well understood since homogenous glycoproteins (glycoforms) cannot be obtained by purification in sufficient quantities. Thus, convergent synthetic approaches were developed providing homogenous glycoproteins via native chemical ligation and subsequent refolding. The demanding synthetic routes towards glycoforms could be significantly shortened in the first funding period leading to the first libraries of natural glycoforms of IL-6 and saposin D. All synthetic glycoforms were biologically active. For the lysosomal adapter protein saposin D several bioactivities related to membrane remodelling were found to be carbohydrate-dependent.In the second funding period we aim to further improve the synthesis of glycoforms of IL-6 and saposins by using chemoenzymatic methods in the synthesis of N-glycans and N-glycopeptides. The pimary goal is the assembly of a representative library of glycoforms of all four human sapsins. Due to their structural and functional homology it can be assumed that also the saposins A-C have bioactivities with carbohydrate-dependency, which should be revealed by established assays systems. The in vivo functions of saposins are correlated with the formation of saposin oligomers complexed with lipids. Since these complexes have been investigated only with non-glycosylated saposins, the glycosylated complexes will be targeted specifically and characterized subsequently.

糖蛋白的功能经常受其碳水化合物部分的调节。这些糖部分表现出天然的微观异质性。由于无法通过纯化获得足够数量的同质糖蛋白（糖型），因此微观异质性的后果尚不清楚。因此，开发了聚合合成方法，通过天然化学连接和随后的重折叠提供同质糖蛋白。在第一个资助期内，可以显着缩短糖型的合成路线，从而产生第一个 IL-6 和 saposin D 天然糖型文库。所有合成糖型都具有生物活性。对于溶酶体接头蛋白saposin D，发现与膜重塑相关的几种生物活性是碳水化合物依赖性的。在第二个资助期中，我们的目标是通过在N-聚糖和N-糖肽的合成中使用化学酶法来进一步改进IL-6和saposin的糖型合成。主要目标是组装所有四种人类皂苷的代表性糖型文库。由于其结构和功能同源性，可以假设皂苷 A-C 也具有碳水化合物依赖性生物活性，这应该通过已建立的测定系统来揭示。 saposin 的体内功能与与脂质复合的saposin 寡聚物的形成相关。由于仅用非糖基化皂苷研究了这些复合物，因此将特异性靶向糖基化复合物并随后进行表征。

项目成果

N-Metallocenoylsphingosines as targeted ceramidase inhibitors: Syntheses and antitumoral effects.

N-金属茂酰鞘氨醇作为靶向神经酰胺酶抑制剂：合成和抗肿瘤作用

• DOI: 10.1016/j.bioorg.2020.103703
• 发表时间: 2020
• 期刊: Bioorganic chemistry
• 影响因子: 5.1
• 作者: M. Rothemund;A. Bär;F. Klatt;S. Weidler;L. Köhler;C. Unverzagt;C. D. Kuhn;R. Schobert
• 通讯作者: R. Schobert

Strategies for the highly efficient synthesis of erythropoietin N‐glycopeptide hydrazides

促红细胞生成素Nâ糖肽酰肼的高效合成策略

• DOI: 10.1002/psc.3283
• 发表时间: 2020
• 期刊: Journal of Peptide Science
• 影响因子: 2.1
• 作者: M. Hessefort;H. Hessefort;S. Seeleithner;A. Gross;M. Lott;D. Rau;L. Kern;C. Unverzagt
• 通讯作者: C. Unverzagt