SULFUR-SULFUR BRIDGING IN SOLID-PHASE PEPTIDE SYNTHESIS

描述：二硫键在折叠和折叠过程中起着至关重要的作用 许多重要胞外肽和蛋白质的结构稳定性 分子；这些键的重要性在于它们以共价方式交联 在线性序列中分开的多肽链的部分 在三个维度上走到一起。目前的研究计划建立在 我们实验室在温和化学方法方面的孪生专业知识 固相多肽合成和有机硫化学 授权期我们已经制定了许多新颖和有用的程序 用于选择性保护半胱氨酸残基和控制产生 多肽中的硫-硫键。可以在多肽的情况下执行步骤 保持锚定在聚合物载体上，从而利用 有利于分子内环化的伪稀释现象。 溶液环化反应和由新型聚合物结合试剂介导的环化反应是 也很有意思。我们的多方面方法评估了一系列 硫基保护和/或活化基，锚链，温和 解除保护和/或解理和/或氧化的条件，以及聚合物 支持对这些持续挑战的适用性。二 有选择地解锁、伴随或跟随预定残基 通过共氧化或通过“定向”技术来创建成对的 交叉链接。对照实验检验反应的相对影响 条件、树脂替代水平和载体特性 单体材料的产率和纯度。最好的方法被应用于 实现了具有一到三个二硫化物的目标分子的合成， 包括催产素、生长抑素、芋螺毒素和中性粒细胞防御素。AS 我们能够计算出母体结构的合成，并且作为 合适的，它们的平行和/或反平行二聚体，类似物是 考虑其中一个或多个二硫化物被移除、等位元替换， 环的大小减小或增加，构象刚性越大 引入，和/或二硫化物被故意错配。一项建议 三硫化物的改性利用了这一研究的一些最新进展 程序。合成肽的共价结构将是 核实后，将研究二级和三级结构 已建立的生物物理技术和生物活动将 下定决心。最终，合理设计的类似物的化学合成 我们的靶向二硫键多肽，以及其他类似的工作 系统，可能导致更有效、更有选择性和更持久的药物。

DESCRIPTION: Disulfide bridges play a crucial role in the folding and structural stabilization of many important extracellular peptide and protein molecules; the importance of these bonds is that they cross-link covalently portions of the polypeptide chain which are apart in the linear sequence but come together in three dimensions. The present research program builds on the twin expertises of our laboratories in mild chemical methods for solid-phase peptide synthesis and in organosulfur chemistry; within this granting period we have developed a number of novel and useful procedures for the selective protection of cysteine residues and controlled creation of sulfur-sulfur bonds in peptides. Steps can be carried out while a peptide remains anchored to a polymeric support, thereby taking advantage of the pseudo-dilution phenomenon which favors intramolecular cyclization. Solution cyclizations and those mediated by novel polymer-bound reagents are also of interest. Our multi-faceted approach assesses a repertoire of sulfhydryl protecting and/or activating groups, anchoring linkages, mild conditions for deprotection and/or cleavage and/or oxidation, and polymeric supports for applicability to these continuing challenges. Two predetermined residues are selectively deblocked, accompanied or followed either by co-oxidation or by "directed" techniques to create a pairwise cross-link. Controlled experiments test the relative influence of reaction conditions, resin substitution level, and support characteristics on the yield and purity of monomeric material. The best methods are applied to achieve the syntheses of target molecules with one to three disulfides, including oxytocin, somatostatins, conotoxins, and neutrophil defensins. As we are able to work out syntheses of the parent structures, and as appropriate, their parallel and/or anti-parallel dimers, analogs are contemplated where one or more disulfide is removed, isosterically replaced, ring size is decreased or increased, more conformational rigidity is introduced, and/or disulfides are intentionally mispaired. A proposed trisulfide modification exploits some recent advances from this research program. The covalent structures of the synthetic peptides will be verified, the secondary and tertiary structures will be studied by established biophysical techniques, and biological activities will be determined. Ultimately, chemical synthesis of rationally-designed analogs of our targeted disulfide-containing peptides, and similar work in other systems, may lead to more potent, selective, and longer-lasting drugs.