DESIGN & SYNTHESIS OF PEPTIDOMIMETIC COMPOUNDS

本子项目是利用由NIH/NCRR资助的中心赠款提供的资源的众多研究子项目之一。子项目和研究者（PI）可能已经从另一个NIH来源获得了主要资金，因此可以在其他CRISP条目中表示。列出的机构是中心的，不一定是研究者的机构。本研究集中在有机化学与化学生物学的交叉领域。生物系统可以从有机化学家的角度和使用合成的工具来研究，这一理念产生了新的想法，有助于提高我们对化学生物学的认识。反过来，在为探测生物系统而设计的试剂合成中遇到的问题往往需要开发新的合成方法。这两个领域的基础研究相辅相成，相互促进。我们主要的拟肽项目之一集中在设计和合成聚l -脯氨酸II型（PPII）二级结构的模拟物。PPII模拟物的合成作为这些细胞信号通路的激动剂或拮抗剂，有助于揭示复杂的信号级联反应，并成为药物的潜在起点。我们的PPII设计策略是通过理解全脯氨酸肽的构象适当关系来指导的，其中，由于吡啶环的约束，角phi被限制在约-75°，而psi角被限制在约145°，这是由于pseudo-A（1,3）应变的最小化。我们利用这些构象约束元件从模板氨基酸（PTAAs）合成PPII模拟物。我们的实验室已经开发了一个广泛的项目，专注于ptaa的合成以及PPII模拟组合文库的开发。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This research is centered at the interface of organic chemistry and chemical biology. From a philosophy that biological systems may be studied from an organic chemist''s perspective and using the tools of synthesis, come new ideas which help advance our knowledge of chemical biology. In turn, problems encountered in the synthesis of agents designed to probe biological systems often necessitate the development of new synthetic methodology. Fundamental research in these two areas thus strengthen and complement each other. One of our main peptidomimetic projects is focused on the design and synthesis of mimics of the poly-L-proline type II (PPII) secondary structure. The synthesis of PPII mimics that act as agonists or antagonists of these cell signaling pathways are useful in unraveling the complex signaling cascades as well as being potential starting points for pharmaceuticals. Our PPII design strategy is guided by an understanding of the conformational proper tie s of all-proline containing peptides in which the angle phi is restricted to ca. -75: by the constraints of the pyrrolidine ring while the psi angle is constrained to ca. 145: by the minimization of pseudo-A(1,3) strain. We utilize these conformational constraint elements to synthesize PPII mimics from templated amino acids (PTAAs). Our laboratory has developed an extensive program focused on the synthesis of PTAAs as well as the development of PPII mimic combinatorial libraries.