使用新型易酸苯并呋喃酮胺 (ALBA) 连接剂揭示 RFamide 功能的重要作用

IF 1.5 4区 化学 Q3 CHEMISTRY, MULTIDISCIPLINARY
Gemma Mudd, Megan Hendrikse, Steven Shave, Douglas R Houston, Robert P Millar, Manfred Auer
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引用次数: 0

摘要

RFamide 肽家族是一类重要的 GPCR 配体神经肽,具有广泛的生物功能。虽然已经合成了该肽类中高度保守的 C 端 RFamide 基团的许多类似物并阐明了它们的功能意义,但对结构活性关系的进一步探索仍有价值。我们开发了一种用于固相肽合成(SPPS)的新型连接剂,它能锚定胺功能化化合物,以便进一步加工。酸性苯并呋喃酮基胺(ALBA)连接体(5-(3-氨基丙基氨基甲酰基)-2-[[叔丁基(二苯基)硅]氧甲基]苯甲酸)与基于 Fmoc 的 SPPS 兼容,并具有两种裂解模式。作为概念验证,我们使用 ALBA 连接器成功合成了 GPCR54 的天然配体 Kisspeptin 10 的新型类似物,用 RFamine 取代了天然 RFamide 基团。对含胺类似物的生物学评估显示,该基团与受体激活不相容。
本文章由计算机程序翻译,如有差异,请以英文原文为准。

Revealing the Indispensable Role of the RFamide Functionality using a Novel Acid Labile Benzofuranone based Amine (ALBA) Linker

Revealing the Indispensable Role of the RFamide Functionality using a Novel Acid Labile Benzofuranone based Amine (ALBA) Linker

The RFamide family of peptides represents an important class of GPCR ligand neuropeptides covering a wide range of biological functions. While many analogues of the highly conserved C-terminal RFamide motif within this peptide class have been synthesized and their functional significance elucidated, additional exploration of the structure activity relationship is of value. We have developed a novel linker for solid phase peptide synthesis (SPPS) which is able to anchor amine functionalised compounds for further elaboration. The acid labile benzofuranone based amine (ALBA) linker (5-(3-aminopropylcarbamoyl)-2-[[tert-butyl(diphenyl)silyl]oxymethyl]benzoic acid) is compatible with Fmoc based SPPS and has two cleavage modes. As a proof of concept, the ALBA linker was used to successfully synthesise a novel analogue of Kisspeptin 10, the natural ligand for GPCR54, whereby the natural RFamide motif was replaced with an RFamine. Biological evaluation of the amine-containing analogue revealed that the group is not compatible with receptor activation.

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来源期刊
Helvetica Chimica Acta
Helvetica Chimica Acta 化学-化学综合
CiteScore
3.00
自引率
0.00%
发文量
60
审稿时长
2.3 months
期刊介绍: Helvetica Chimica Acta, founded by the Swiss Chemical Society in 1917, is a monthly multidisciplinary journal dedicated to the dissemination of knowledge in all disciplines of chemistry (organic, inorganic, physical, technical, theoretical and analytical chemistry) as well as research at the interface with other sciences, where molecular aspects are key to the findings. Helvetica Chimica Acta is committed to the publication of original, high quality papers at the frontier of scientific research. All contributions will be peer reviewed with the highest possible standards and published within 3 months of receipt, with no restriction on the length of the papers and in full color.
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