Gearing up for receptor binding: Tryptophan-derived diaryl amino acids in bioactive peptides

为受体结合做好准备：生物活性肽中色氨酸衍生的二芳基氨基酸

• 批准号: 440373037
• 负责人: Professor Dr. Armin Geyer
• 金额: --
• 依托单位: Fachgebiet Organische Chemie
• 依托单位国家: 德国
• 项目类别: Research Grants
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/440373037?language=en
• 关键词: Gearing; up; receptor; binding; Tryptophan

The amino acid L-tryptophan (Trp) is a building block of several neuropeptides that mediate important physiological processes. Trp has an extended pi-system that interacts with the binding pocket of the protein receptors and accounts for much of the binding affinity and selectivity of a peptide. Although structural modifications of the indole ring of Trp mostly cause a dramatic loss of biological activity, a suitable Trp derivative on the other hand can be key to transform a peptide into a drug. Beyond the difficulty of selecting an appropriate Trp mimetic for a certain purpose, the choice is limited because only few preparative protocols are compatible with the sensitive indole side chain of Trp. Therefore, the synthesis of a diverse or even complete group of amino acids representing all possible side chain orientations of Trp is a relevant step towards the idea of the synthesis of the bioactive conformation of Trp-containing peptides.We recently made accessible a new class of Trp-derived amino acids by improving on the synthetic methods that were developed by others for the preparation of beta,beta-diaryl amino acids bearing simple aryl groups. The characteristic feature of the new Trp mimetics is their restricted indole mobility without modifications of the indole ring system. The orientation of the two interlocked aryl propellers of the diaryl amino acid and their interdependent rotational mobility is accessible by NMR spectroscopy. A focus of this project will be laid on the experimental quantification of the relative mobility of the two aryl groups and their response to differing peptide environments. The process known as “steric gearing” prevents the unspecific pi-stacking that is observed with other extended aryl side chains. The correlation between the steric demand of the beta-indoylated amino acids and their influence on the peptide structure will be investigated here. In spite of its potential to control peptide conformation, steric gearing was not systematically investigated as a design principle for bioactive peptides before. In a preliminary experiment we studied two stereoisomers of beta-phenylated Trp which differ only in the relative orientation of their indole group, yet cause complementary selectivities in peptides binding to the ghrelin receptor. In a second testing system, the affinity of ACTH-type peptides for the melanocortin receptor 2 (MC2R) increased by a factor of nearly five when containing one of the beta-indoylated alpha-amino acids. Our cooperation partners will further investigate the promising bioactivities while this research project is dedicated to develop chemical methods to improve the accessibility of Trp-derived beta-branched alpha-amino acids.

氨基酸L-色氨酸（Trp）是介导重要生理过程的几种神经肽的构建块。色氨酸具有扩展的π-系统，其与蛋白质受体的结合口袋相互作用，并占肽的结合亲和力和选择性的大部分。虽然Trp的吲哚环的结构修饰主要导致生物活性的显著损失，但另一方面，合适的Trp衍生物可以是将肽转化为药物的关键。除了难以为特定目的选择合适的Trp模拟物之外，选择是有限的，因为只有少数制备方案与Trp的敏感吲哚侧链相容。因此，合成代表Trp所有可能的侧链取向的多种或甚至完整的氨基酸组是合成含Trp肽的生物活性构象的想法的相关步骤。带有简单芳基的β-二芳基氨基酸。新的色氨酸模拟物的特征在于它们的吲哚流动性受限，而不改变吲哚环系统。的二芳基氨基酸的两个互锁的芳基推进器和它们的相互依赖的旋转流动性的取向是可访问的NMR光谱。该项目的重点将放在两个芳基基团的相对迁移率的实验定量及其对不同肽环境的响应上。被称为“空间齿轮”的过程防止了在其他延伸的芳基侧链中观察到的非特异性π堆积。这里将研究β-吲哚基化氨基酸的空间需求与它们对肽结构的影响之间的相关性。尽管它的潜力，以控制肽的构象，空间齿轮没有系统地研究作为生物活性肽的设计原则之前。在一个初步的实验中，我们研究了两个立体异构体的β-苯基化的色氨酸不同的只是在其吲哚基团的相对取向，但在肽结合的生长激素释放肽受体的互补选择性。在第二个测试系统中，当含有β-吲哚基化α-氨基酸之一时，ACTH型肽对黑皮质素受体2（MC 2 R）的亲和力增加了近5倍。我们的合作伙伴将进一步研究有前景的生物活性，而本研究项目致力于开发化学方法来提高色氨酸衍生的β-支链α-氨基酸的可及性。