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

氨基酸L-色氨酸(Trp)是调节重要生理过程的几种神经肽的组成部分。Trp有一个扩展的pi-系统，它与蛋白质受体的结合口袋相互作用，并解释了多肽的结合亲和力和选择性的很大一部分原因。虽然色氨酸吲哚环的结构修饰大多会导致生物活性的急剧丧失，但另一方面，合适的色氨酸衍生物可能是将多肽转化为药物的关键。除了为特定目的选择合适的色氨酸模拟物的困难之外，选择是有限的，因为只有很少的制备方案与色氨酸的敏感吲哚侧链相容。因此，合成代表色氨酸所有可能侧链取向的不同甚至完整的氨基酸基团是朝着合成含有色氨酸的生物活性构象的思想迈出的相关的一步。最近，我们通过改进其他人的合成方法来制备含有简单芳基的β，β-二芳基氨基酸，从而获得了一类新的色氨酸衍生氨基酸。新的色氨酸模拟物的特征是它们在不改变吲哚环系的情况下限制了吲哚的迁移率。二芳基氨基酸的两个相互连锁的芳基推进器的取向和它们相互依赖的旋转迁移率可以通过核磁共振光谱来获得。本项目的重点将放在对两个芳基的相对迁移率及其对不同多肽环境的响应的实验量化上。这一过程被称为“立体啮合”，可防止观察到的其他扩展芳基侧链的非特定聚酰亚胺堆积。本文将研究β-吲哚基氨基酸的空间需求与其对多肽结构的影响之间的关系。尽管空间配位具有控制多肽构象的潜力，但作为生物活性多肽的一种设计原则，以前并没有系统的研究。在初步实验中，我们研究了两种β-苯基化色氨酸的立体异构体，它们只在吲哚基团的相对取向上不同，但在与Ghrelin受体结合的多肽中引起互补的选择性。在第二个测试系统中，ACTH型多肽与黑素皮质素受体2(MC2R)的亲和力在含有一种β-吲哚基化的α-氨基酸时增加了近五倍。我们的合作伙伴将进一步研究有前景的生物活性，同时该研究项目致力于开发化学方法，以提高色氨酸衍生的β-支链α-氨基酸的可及性。

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.