Oxadiazole grafts in peptide macrocycles

尤丁博士的团队开发了一种通用的方法，通过容易获得的成分之间的反应，即线性多肽、醛和(N-异氰氨基)三苯基膦(PINC)之间的反应，快速获得结构多样化的大环肽。这种方法的一个独特和使人能够实现的特征是形成一个前所未有的基序，其形式为连续的非酰胺化N-末端氨基、可变醛和直接插入到肽骨架中的1，3，4-恶二唑三联体。这种新的连接显示出非常保守的构象几何结构，独立于肽或醛成分，并作为内环控制元件稳定转角基序，从而促进被动膜的通透性。这反过来又有利于含恶二唑的大环的口服生物利用度。在许多生物活性多肽中都存在着？转，这支持了这一方法学在开发新的疗法和生物探针方面的应用。

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.