Sugar-modified foldamers as conformationally defined and biologically distinct glycopeptide mimics.
Sugar-modified foldamers as conformationally defined and biologically distinct glycopeptide mimics.
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DOI：
10.1002/anie.201304239
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发表时间：
2013-09-23
影响因子：
16.6
通讯作者：
Chakraborty, Tushar Kanti
中科院分区：
文献类型：
--
作者：
Siriwardena, Aloysius;Pulukuri, Kiran Kumar;Kandiyal, Pancham S.;Roy, Saumya;Bande, Omprakash;Ghosh, Subhash;Garcia Fernandez, Jose Manuel;Martin, Fernando Ariel;Ghigo, Jean-Marc;Beloin, Christophe;Ito, Keigo;Woods, Robert J.;Ampapathi, Ravi Sankar;Chakraborty, Tushar Kanti
关键词：
据预测，超过一半的真核蛋白质被糖基化，并且现在已经确定，蛋白质与聚糖的共翻译和翻译后修饰可以对其折叠、稳定性以及最终的功能产生巨大的影响。 [1]因此，人们投入了大量的精力来描述附加碳水化合物对溶液中蛋白质和肽的构象偏好的影响，反之亦然，[2]以及了解它们与其同源受体的相互作用。[3]这些努力并不简单，只有在少数经过充分研究的案例中才可能成功地使这些过程合理化。 [4]对这些问题的重要见解是从糖复合物模拟物的研究中获得的，其与细胞靶标的相互作用可以影响广泛的生理现象，包括受精、免疫反应、宿主-病原体相互作用、细胞生长和肿瘤转移。 [1]然而，尽管这些目标在寻求基于碳水化合物的治疗方法中非常重要，但成功将结构明确的糖肽的生物学功能与其二级结构关联起来的尝试相对较少[2-4]。 [5]在此，我们研究了附加糖部分对源自 δ-糖氨基酸 (δ-SAA) 的肽折叠体构象行为的影响。 [6]折叠体的研究过去有助于启发我们对生物聚合物的首选二级结构和生物活性的起源的理解。 [7]考虑到糖蛋白的内源性和治疗重要性，我们对描述糖基化对肽折叠体二级结构的影响的报告的缺乏感到震惊。 [8]新合成的 δ-SAA 衍生糖折叠体的两个家族中附加的糖确实对肽折叠体主链的优选构象起着决定性作用，而且，即使在水中，也能看到这种作用，这种情况要少见得多。 [9]此外，每种糖折叠体表现出的构象差异反映在它们与选定靶标的独特且对比的相互作用中，这些靶标包括凝集素伴刀豆球蛋白 A (ConA)[10a] 和大肠杆菌 (E. coli)。[10b]本文研究的 δ-SAA 衍生折叠体家族（在文中注释为顺式和反式）在立体中心的构型方面彼此不同。其组成部分 δ-SAA 部分的呋喃环 C2：具有“2S”构型的称为顺式折叠体，具有“2R”构型的称为反式折叠体（方案 1）。先前的研究表明，在有机溶剂中，顺式折叠体采用类似于传统β-转角的构象，而反式折叠体的二级结构取决于其组成呋喃环的取代基模式。 [11]基于 δ-SAA 的目标家族
It is predicted that over half of all eukaryotic proteins are glycosylated, and it is now well-established that co-and posttranslational modification of proteins with glycans can have dramatic consequences on their folding, stability, and ultimately their function.[1] Considerable effort has thus been invested in delineating the impact of appended carbohydrates on the conformational preferences of proteins and peptides in solution and vice versa,[2] and also in understanding their interactions with their cognate receptors.[3] These endeavours are not straightforward, and success in rationalizing such processes has been possible only in a handful of well-studied cases.[4] Important insights into such questions have been gleaned from the study of glycoconjugate mimetics, whose interactions with cellular targets can impact a wide range of physiological phenomena, including fertilization, immune response, host–pathogen interactions, cell growth, and tumor metastasis.[1] However, attempts to successfully correlate biological functions of structurally well-defined glycopeptides with their secondary structures have been relatively sparse,[2–4] despite the importance of such targets in the quest for carbohydrate-based therapeutics.[5] Herein we examine the effects of appended sugar moieties on the conformational behavior of peptide foldamers derived from δ-sugar amino acids (δ-SAAs).[6] The study of foldamers has in the past helped enlighten our understanding of the origins of the preferred secondary structures and biological activities of biopolymers.[7] Considering the endogenous and therapeutic importance of glycoproteins, we were struck by the dearth of reports describing the impact of glycosylation on the secondary structures of peptide foldamers.[8] Appended sugars in the two families of newly synthesized δ-SAA-derived glycofoldamers indeed play a defining role on the preferred conformations of the peptide foldamer backbones and, far less commonly, are seen to do so even in water.[9] Furthermore, the differences in conformation manifested by each glycofoldamers are shown to be mirrored in their distinct and contrasting interaction with selected targets including the lectin Concanavalin A (ConA)[10a] and the bacterium Escherichia coli (E. coli).[10b]The families of δ-SAA-derived foldamers targeted for investigation herein, annotated cis-and trans-in the text, differ from one another in the configuration of the stereocenter at C2 of the furanoid rings of their constituent δ-SAA moieties: those with the “2S” configuration designated cisfoldamers, and those with “2R”, trans-foldamers (Scheme 1). Previous work has shown that in organic solvents, cisfoldamers adopt conformations reminiscent of a conventional β-turn, whereas the secondary structures of trans-foldamers are dependent on the substituent pattern of their constituent furanoid rings.[11] The targeted families of δ-SAA-based
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影响因子：
2.9
作者：
Larkin A;Imperiali B
通讯作者：
Imperiali B
影响因子：
5.1
作者：
Korea, Charalampia-Georgia;Badouraly, Reana;Beloin, Christophe
通讯作者：
Beloin, Christophe
影响因子：
3.6
作者：
Claridge, TDW;Long, DD;Smith, MD
通讯作者：
Smith, MD
DOI：
10.1073/pnas.93.23.12759
发表时间：
1996-11-12
影响因子：
11.1
作者：
Live, DH;Kumar, RA;Danishefsky, SJ
通讯作者：
Danishefsky, SJ
影响因子：
15
作者：
Kuemin, Michael;Sonntag, Louis-Sebastian;Wennemers, Helma
通讯作者：
Wennemers, Helma