Oxadiazole grafts in peptide macrocycles

Yudin博士的小组开发了一种通用的方法，通过容易获得的组分之间的反应，即线性肽，醛和（N-异氰基亚氨基）三苯基膦（Pinc），快速获得结构多样的大环肽。这种方法的独特和使能特征涉及以直接插入肽骨架中的连续非酰胺化N-末端氨基、可变醛和1，3，4-恶二唑三联体的形式形成前所未有的基序。这种新的连接显示出非常保守的构象几何形状，独立的肽或醛组分，并作为一个内环控制元件，稳定转动基序，从而促进被动膜渗透性。这反过来又促进了含恶二唑大环化合物的口服生物利用度。β-转角存在于许多生物活性肽中，支持该方法用于开发新的治疗剂和生物探针。

Dr. Yudin's group has developed a versatile approach to rapidly access structurally diverse macrocyclic peptides via a reaction between readily accessible components, namely, a linear peptide, aldehyde, and (N-isocyanimino) triphenylphosphorane (Pinc). A unique and enabling feature of this approach involves the formation of an unprecedented motif in the form of a contiguous non-amidated N-terminal amino group, variable aldehyde, and 1,3,4-oxadiazole triad inserted directly into the peptide backbone. This new linkage displays a remarkably well-conserved conformational geometry, independent of the peptidic or aldehyde components, and serves as an endocyclic control element that stabilizes turn motifs thereby promoting passive membrane permeability. This, in turn, facilitates oral bioavailability of oxadiazole-containing macrocycles. ß-Turns are present in a number of biologically active peptides, supporting the application of this methodology for the development of new therapeutics and biological probes.