Heterochiral Dipeptides of Chimeric Cyclic Amino Acids

描述(申请人提供)：本研究的目标是开发各种多肽“构象模板”作为分子探针，即满足至少三个要求的相对刚性支架： (I)具有有限的三维结构(有限的明确的三维构象)； (Ii)可随时以综合方式取用，及 (Iii)能够独特地定向多肽侧链(α-β和β-伽马键)，据信这些侧链在多肽-受体相互作用期间传递大部分信息。 这项建议提供了基于嵌合氨基酸类似物的四环构象多肽模板，这些氨基酸类似物包括：脯氨酸、氮杂丙氨酸、异丙醇酸、氮杂丙酸、异丙基丙酸和异丙基丙酸，作为新的“特权支架”(嵌合氨基酸结合了两种氨基酸的性质，例如结合了D-丙氨酸和L-丙氨酸的空间性质的氨基异丁酸)。所选择的配体足够小，可以通过密度泛函计算确定势能面，并计算能量极小值及其相对能量学。这为评估数据分析中要考虑的构象的数量和相对能量提供了基础。新的化合物将被设计和合成，以引入共价约束，能够以最大程度的保真度对齐识别基序的氨基酸侧链，并通过分子建模通过虚拟筛选寻找与趋化因子受体结合部位缺乏负空间相互作用的化合物。电化学助剂的新用途将允许在组装环状模板后连接侧链。开发特异性抑制的治疗靶点是CXCR4受体，具有潜在的抗病毒和肿瘤学应用。

DESCRIPTION (provided by applicant): The objective of this research is the development of a variety of peptide "conformational templates" as molecular probes, i.e. relatively rigid scaffolds that satisfy at least three requirements: (i) possess limited 3D structures (limited well-determined 3D conformers); (ii) be readily accessible synthetically, and (iii) able to uniquely orient the peptide side chains (both alpha-beta and beta-gamma bonds) that are believed to transfer most of the information during peptide-receptor interactions. This proposal offers tetracyclic conformational peptide templates based on chimeric amino acid analogs of proline, azaproline, pipecolic, azapipecolic, nipecotic and isonipecotic acids as novel "privileged scaffolds" (chimeric amino acids combine the properties of two amino acids, an example is aminoisobutyric acid that combines the steric properties of D- and L-alanine). The ligands chosen for study are sufficiently small that the potential energy surface can be determined by DFT calculations, and the energy minima and their relative energetics evaluated. This provide the basis for evaluating the number and relative energetics of conformers to be considered in data analysis. Novel compounds will be designed and synthesized to introduce covalent constraints that are able to align the amino-acid side chains of the recognition motif with greatest fidelity and lack of negative steric interaction with the binding site of chemokine receptors will be sought by virtual screening through molecular modeling. Novel uses of electrochemical auxiliaries will allow pendant side chains to be attached after the cyclic templates are assembled. The therapeutic target for development of specific inhibition is the CXCR4 receptor with potential applications as an antiviral and in oncology.