C-terminal tails mimicking bioactive intermediates cause different plasma degradation patterns and kinetics in neuropeptides γ-MSH, α-MSH, and neurotensin.,Journal of Peptide Science

当前位置： X-MOL 学术 › J. Pept. Sci. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

C-terminal tails mimicking bioactive intermediates cause different plasma degradation patterns and kinetics in neuropeptides γ-MSH, α-MSH, and neurotensin.
Journal of Peptide Science ( IF 1.8 ) Pub Date : 2020-08-18 , DOI: 10.1002/psc.3279
Luana Palazzi ₁ , Antonella Pasquato ₂ , Mattia Vicario ₃ , Alexandre Roulin ₄ , Patrizia Polverino de Laureto ₁ , Laura Cendron ₃

Affiliation

Peptides are attractive drugs because of their specificity and minimal off‐target effects. Short half‐lives are within their major drawbacks, limiting actual use in clinics. The golden standard in therapeutic peptide development implies identification of a minimal core sequence, then modified to increase stability through several strategies, including the introduction of nonnatural amino acids, cyclization, and lipidation. Here, we investigated plasma degradations of hormone sequences all composed of a minimal active core peptide and a C‐terminal extension. We first investigated pro‐opimelanocortin (POMC) γ2/γ3‐MSH hormone behavior and extended our analysis to POMC‐derived α‐melanocyte stimulating hormone/adrenocorticotropic hormone signaling neuropeptides and neurotensin. We demonstrated that in all the three cases analyzed in this study, few additional residues mimicking the natural sequence alter both peptide stability and the mechanism(s) of degradation of the minimal conserved functional pattern. Our results suggest that the impact of extensions on the bioactivity of a peptide drug has to be carefully evaluated throughout the optimization process.

中文翻译：

模仿生物活性中间体的C末端尾巴在神经肽γ-MSH，α-MSH和神经降压素中引起不同的血浆降解模式和动力学。

肽由于其特异性和最小的脱靶效应而成为有吸引力的药物。半衰期短是其主要缺点，限制了临床实际使用。治疗性肽开发的黄金标准意味着鉴定最小的核心序列，然后通过几种策略进行修饰以增加稳定性，包括引入非天然氨基酸，环化和脂质化。在这里，我们研究了血浆中激素序列的降解，这些降解均由最小的活性核心肽和C末端延伸组成。我们首先研究了前庚二酸珊瑚素（POMC）γ2/γ3-MSH激素的行为，并将我们的分析扩展到POMC衍生的α-黑素细胞刺激激素/促肾上腺皮质激素信号神经肽和神经降压素。我们证明了在本研究中分析的所有三个案例中，几乎没有模仿天然序列的残基改变了肽的稳定性和最小保守功能模式的降解机理。我们的结果表明，在整个优化过程中，必须仔细评估延伸对肽类药物生物活性的影响。

更新日期：2020-10-02

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11