PROBING RECEPTOR BOUND CONFORMATIONS BY CYCLIC PEPTIDES

提出了一种组合方法作为阐明问题的一般方法。 多肽配体的受体结合构象。一座图书馆 含有双脲的模板受限环肽将被 合成的。这些环肽将用来呈现相同的 不同构象的识别元件。图书馆将会是 筛选与RGD结合整合素的高亲和力结合 (alpha5beta1、alphaIIbbeta3和alphaVbeta3)。后续结构 分析高结合亲和力的多肽类药物将使 对整合素结合的构象的阐明是有用的 开发相关治疗药物。这一总体方法 涉及模板受限环肽的文库可以是 适用于任何带有短肽配体的受体。

A combinatorial approach is proposed as a general method for elucidating the receptor-bound conformation of peptide ligands. A library of template-constrained cyclic peptides incorporating bis-ureas will be synthesized. These cyclic peptides will serve to present the same recognition elements in different conformations. The library will be screened for high affinity binding to the RGD-binding integrins (alpha5beta1, alphaIIbbeta3, and alphaVbeta3). Subsequent structural analysis of the high binding affinity peptidomimetics will enable the elucidation of the integrin-bound conformations which are useful for the development of relevant therapeutic drugs. This general approach involving libraries of template-constrained cyclic peptides can be applied to any receptor with a short peptidyl ligand.