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Modified multivalent poly-N-acetyllactosamine glycans as novel ligands of human galectin-3

修饰多价聚-N-乙酰基乳糖胺聚糖作为人半乳糖凝集素-3的新型配体

基本信息

批准号：
266459926
负责人：
Professor Dr. Lothar Elling
金额：
--
依托单位：
Lehrstuhl für Biotechnologie
依托单位国家：
德国
项目类别：
Research Grants
财政年份：
2015
资助国家：
德国
起止时间：
2014-12-31 至 2017-12-31
项目状态：
已结题

来源：
https://gepris.dfg.de/gepris/projekt/266459926?language=en
关键词：
Modified multivalent poly acetyllactosamine glycans

项目摘要

The functional role of carbohydrates in biological systems has been an area of intense research in recent years. Carbohydrates, formerly considered as inert molecules protecting the cell surface, are now recognized as important information transmitters in cellular processes. Cell surface glycoproteins and glycolipids can serve as protein ligands, thereby providing an anchor for intercellular adhesion or a receptor for viral and bacterial invasion. Their role in regulation of differentiation processes is generally acknowledged. Glycoconjugates and glycomimetics have, therefore, a significant pharmaceutical potential. For physiological applications of carbohydrates two important issues have to be addressed: i) multivalency - dictated by the fact of rather weak carbohydrate-protein interactions occurring in natural structures (multiantennary glycoproteins); ii) stability of structure and protection from cleavage of natural O-glycosidic bonds by numerous glycosidases in the organism. This obstacle can be overcome by preparation of artificial multivalent neoglycoconjugates and by introduction of unnatural carbohydrate linkages leading to a glycomimetic concept. Chemical extension of complex multivalent or multi-linear glycoclusters is virtually impossible due to high complexity and intrinsic properties of carbohydrates, e.g., presence of a large number of rather similar OH groups that can only be distinguished by complex and labor-demanding protection/deprotection strategy. Enzymatic methods have already become a viable alternative to organic chemistry in the synthesis of complex carbohydrate structures, especially due to their selectivity and simplicity. Here, in contrast to glycosidases, glycosyltransferases offer an ideal tool for selective modification of such structures due to their absolute stereoselectivity and high regioselectivity. Since these enzymes modify complex multi-antennary structures in nature they are able to work on multi-linear and multivalent glycoclusters containing LacNAc structures. In the present joint proposal of the Elling and Kren group glycosyltransferases, glycosynthases and galactose oxidase as glycan modifying enzyme will be applied to create a library of modified poly-LacNAc conjugated to stable linkers. Complementary approaches and materials from both groups will be used. Selectivity for binding to human galectin-3, an important galectin in tumor progression and angiogenesis, shall be addressed by the synthesis of specific glycan epitopes in cascade reactions of glycosyltransferases. This small library of epitope carrying poly-LacNAc oligomers will be used for the next step addressing their multivalent presentation. This shall be accomplished by selective oxidation of galactose moieties of poly-LacNAc oligomers and subsequent chemical conjugation of epitope carrying poly-LacNAc oligomers. In this way a library of modified unnatural branched poly-LacNAc oligomers will be obtained as potential inhibitors of Gal-3.

近年来，碳水化合物在生物系统中的功能作用一直是研究的热点。碳水化合物以前被认为是保护细胞表面的惰性分子，现在被认为是细胞过程中重要的信息传递者。细胞表面糖蛋白和糖脂可作为蛋白质配体，从而提供细胞间粘附的锚或病毒和细菌侵入的受体。它们在调节分化过程中的作用是公认的。因此，糖缀合物和糖模拟物具有显著的药学潜力。对于碳水化合物的生理应用，必须解决两个重要问题：i）多价性--由天然结构（多触角糖蛋白）中发生的相当弱的碳水化合物-蛋白质相互作用这一事实决定; ii）结构稳定性和保护免受生物体内众多糖苷酶对天然O-糖苷键的切割。这一障碍可以通过制备人工多价新糖缀合物和通过引入非天然碳水化合物键导致糖模拟物概念来克服。复杂多价或多线性糖簇的化学延伸实际上是不可能的，这是由于碳水化合物的高度复杂性和固有性质，例如，存在大量相当相似的OH基团，其只能通过复杂且费力的保护/脱保护策略来区分。酶法已经成为合成复杂碳水化合物结构的有机化学的可行替代方法，特别是由于其选择性和简单性。在这里，与糖苷酶相反，糖基转移酶由于其绝对立体选择性和高区域选择性而提供了用于选择性修饰此类结构的理想工具。由于这些酶修饰自然界中复杂的多触角结构，因此它们能够作用于含有LacNAc结构的多线性和多价糖簇。在Elling和Kren组糖基转移酶、糖苷酶和半乳糖氧化酶作为聚糖修饰酶的本联合提议中，将应用于产生与稳定接头缀合的修饰的聚-LacNAc的文库。将使用两个小组的互补办法和材料。与人半乳凝素-3（肿瘤进展和血管生成中的一种重要半乳凝素）结合的选择性应通过糖基转移酶级联反应中特定聚糖表位的合成来解决。携带聚-LacNAc寡聚物的表位的该小文库将用于解决其多价呈递的下一步骤。这将通过选择性氧化聚-LacNAc寡聚物的半乳糖部分和随后化学缀合携带聚-LacNAc寡聚物的表位来实现。以这种方式，将获得作为Gal-3的潜在抑制剂的修饰的非天然支化聚LacNAc寡聚物的文库。