Structural Motif Descriptors as a Way To Elucidate the Agonistic or Antagonistic Activity of Growth Hormone–Releasing Hormone Peptide Analogues-猫眼课题宝

结构基序描述符作为阐明生长激素的激动或拮抗活性的一种方法——释放激素肽类似物

DOI：

10.1021/acsomega.8b00375

发表时间：

2018

期刊：

ACS Omega

影响因子：

4.1

通讯作者：

中科院分区：

化学3区

文献类型：

作者：

Jeanne Dit Fouque, Kevin;Salgueiro, Luis M.;Cai, Renzhi;Sha, Wei;Schally, Andrew V.;Fernandez-Lima, Francisco

下丘脑神经肽生长激素释放激素（GHRH）类似物的合成是设计新的治疗药物的有效策略。基于GHRH（1-29）序列的氨基酸突变，已经开发了几种有前景的GHRH的合成激动剂和拮抗剂类似物。由于GHRH激动剂或拮抗剂活性的结构信息有限，因此需要能够将肽序列与生物活性相关联的更有效的分析工作流程。在本工作中，三个GHRH激动剂-MR-356，MR-406，和MR-409-和三个GHRH拮抗剂-MIA-602，MIA-606，和MIA-690-进行了研究，以评估氨基酸序列中的取代对结构基序和受体结合亲和力的作用。使用高分辨率捕获离子迁移谱法与质谱法结合，可以观察到大量肽特异性迁移带（或结构基序描述符）与氨基酸序列和起始溶液环境的函数关系。观察到氨基酸取代之间存在直接相关性（即，碱性残基和D/L-氨基酸），结构基序描述符，和生物学功能（即，GHRH激动剂和拮抗剂的受体结合亲和力）。所提出的基于结构基序描述符的工作流程的简单性、容易性和高通量可以显著降低在筛选新的合成肽类似物期间的成本和时间。

The synthesis of analogues of hypothalamic neuropeptide growth hormone–releasing hormone (GHRH) is an efficient strategy for designing new therapeutic agents. Several promising synthetic agonist and antagonist analogues of GHRH have been developed based on amino acid mutations of the GHRH (1–29) sequence. Because structural information on the activity of the GHRH agonists or antagonists is limited, there is a need for more effective analytical workflows capable of correlating the peptide sequence with biological activity. In the present work, three GHRH agonists—MR-356, MR-406, and MR-409—and three GHRH antagonists—MIA-602, MIA-606, and MIA-690—were investigated to assess the role of substitutions in the amino acid sequence on structural motifs and receptor binding affinities. The use of high resolution trapped ion mobility spectrometry coupled to mass spectrometry allowed the observation of a large number of peptide-specific mobility bands (or structural motif descriptors) as a function of the amino acid sequence and the starting solution environment. A direct correlation was observed between the amino acid substitutions (i.e., basic residues andd/l-amino acids), the structural motif descriptors, and the biological function (i.e., receptor binding affinities of the GHRH agonists and antagonists). The simplicity, ease, and high throughput of the proposed workflow based on the structural motif descriptors can significantly reduce the cost and time during screening of new synthetic peptide analogues.