SULFUR-SULFUR BRIDGING IN SOLID-PHASE PEPTIDE SYNTHESIS

描述：二硫键在折叠和 许多重要胞外肽和蛋白质的结构稳定化 分子;这些键的重要性在于它们共价交联 在线性序列中分开但 在三个维度上结合在一起。 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双重专长， 固相肽合成和有机硫化学;在此 在此期间，我们开发了一些新颖实用的程序， 用于半胱氨酸残基的选择性保护和 肽中的硫-硫键。 可以在肽 保持锚定在聚合物载体上，从而利用 伪稀释现象，这有利于分子内环化。 溶液环化和那些由新的聚合物结合试剂介导的环化， 也很有趣。 我们的多方面方法评估了 巯基保护和/或活化基团，锚定键，温和的 脱保护和/或裂解和/或氧化的条件，以及聚合物 支持适用于这些持续的挑战。 两 预定的残基被选择性地去封闭、伴随或跟随 通过共氧化或通过"定向"技术来产生成对的 交联 对照实验测试反应的相对影响 条件、树脂替代水平和载体特性对 单体材料的产率和纯度。 最好的方法应用于 用一至三个二硫化物实现目标分子的合成， 包括催产素、生长抑素、芋螺毒素和中性粒细胞防御素。 作为 我们能够计算出母体结构的合成， 适当地，它们的平行和/或反平行二聚体、类似物被 考虑其中一个或多个二硫化物被除去，等排置换， 环的大小减少或增加，更多的构象刚性， 引入，和/或二硫化物故意错配。 一项拟议 三硫化物修饰利用了这项研究的一些最新进展 程序. 合成肽的共价结构将是 验证后，将通过以下方法研究二级和三级结构： 生物物理技术和生物活动将被 测定 最终，化学合成合理设计的类似物 我们的靶向含二硫键的肽，以及其他类似的工作， 系统，可能会导致更有效，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.