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首页> 外文OA文献 >Synthesis of Novel Amino Acids and Use of Peptides Peptidomimetics Containing Unnatural Amino Acids for the Development of Selective Melanocortin Peptide Antagonists and for the Study of Melanocortin Receptor Signaling
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Synthesis of Novel Amino Acids and Use of Peptides Peptidomimetics Containing Unnatural Amino Acids for the Development of Selective Melanocortin Peptide Antagonists and for the Study of Melanocortin Receptor Signaling

机译：新型氨基酸的合成以及含有非天然氨基酸的肽和拟肽在开发选择性黑皮质素肽拮抗剂和研究黑皮质素受体信号转导中的用途

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摘要

Unnatural amino acids are indispensible tools, not only for the elucidation of molecular mechanisms during the study of the complicated biological system, but also for the development of novel peptide and protein drugs with better efficacy and lower toxicity. Beta-substituted gamma,delta-unsaturated amino acids have been shown to be an important type of novel amino acid because of the terminal double bond which can be converted to many other functionalities. The methodology for the synthesis of syn-beta-substituted gamma,delta-unsaturated amino acids has been developed. However, there is no satisfactory general method for the synthesis of anti-beta-substituted gamma,delta-unsaturated amino acids. Therefore, a general methodology was developed by using the Eschenmoser-Claisen rearrangement for the synthesis of both racemic and optically active anti-beta-substituted gamma,delta-unsaturated amino acids. This rearrangement is highly diastereoselective and good asymmetric induction was obtained with a relatively small C2-symmetric chiral auxiliary (2R,5R)-dimethylpyrrolidine. In an effort to design peptide antagonists that are selective for human melanocortin 4 receptor, highly constrained trans and cis 4-guanidinium proline derivatives were synthesized and incorporated in various melanotropin analogues designed to mimic the endogenous hMC1,4R selective antagonist hASIP (Agouti Signaling Protein) central loop. Biological assays show that some of these analogues are highly selective for hMC1R and/or hMC4R with partial agonist or antagonist activities due to a new beta-turn structure induced by the presence of the constrained amino acids. According to molecular modeling studies, the lowest energy conformations of these selective analogues resemble the NMR solution structure of the hASIP central loop. Therefore, a new template was developed for the rational design of novel selective melanotropin analogues that may have therapeutic potential. To further understand the molecular mechanisms of hMC4R signaling upon agonist activation, an hMC4R selective nonpeptide agonist THIQ and its fluorescent dye labeled derivatives were needed to compare to peptide agonist MTII with regard to receptor phosphorylation, internalization, etc. An improved synthetic method was developed for the efficient synthesis of THIQ. A method for the synthesis of TRITC labeled THIQ derivatives was also developed.
机译：非天然氨基酸是必不可少的工具，不仅用于阐明复杂生物系统研究过程中的分子机制，而且还用于开发具有更好疗效和更低毒性的新型肽和蛋白质药物。 β-取代的γ，δ-不饱和氨基酸已被证明是新型氨基酸的重要类型，因为其末端双键可以转化为许多其他功能。已经开发出合成β-取代的γ，δ-不饱和氨基酸的方法。但是，没有令人满意的通用方法来合成抗β-取代的γ，δ-不饱和氨基酸。因此，通过使用Eschenmoser-Claisen重排开发了用于合成外消旋和旋光的抗β-取代的γ，δ-不饱和氨基酸的通用方法。这种重排是高度非对映选择性的，并且用相对较小的C 2对称手性辅助（2R，5R）-二甲基吡咯烷获得了良好的不对称诱导。为了设计对人类黑皮质素4受体具有选择性的肽拮抗剂，合成了高度受约束的反式和顺式4-胍基脯氨酸衍生物，并将其掺入设计用于模拟内源性hMC1,4R选择性拮抗剂hASIP（Agouti信号蛋白）的各种黑素促生长素类似物中。中央回路。生物学测定表明，由于受约束的氨基酸的存在诱导的新的β-转角结构，这些类似物中的一些对具有部分激动剂或拮抗剂活性的hMC1R和/或hMC4R具有高度选择性。根据分子模型研究，这些选择性类似物的最低能量构象类似于hASIP中央环的NMR溶液结构。因此，开发了一种新模板，用于合理设计可能具有治疗潜力的新型选择性黑素蛋白类似物。为了进一步了解hMC4R激动剂激活后信号转导的分子机制，需要hMC4R选择性非肽激动剂THIQ及其荧光染料标记的衍生物在肽的磷酸化，内在化等方面与肽激动剂MTII进行比较。 THIQ的有效合成。还开发了一种合成TRITC标记的THIQ衍生物的方法。

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    Qu Hongchang;

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  • 年度 2007
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