Adding a C-terminal amino acid prevents the conformational interconversion of plecanatide analogues.

IF 2.6 4区 生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY
ChemBioChem Pub Date : 2025-07-02 DOI:10.1002/cbic.202500237
Guiyang Yao, Yi Zhou, Jingyan Jin, Pingzheng Zhou, Wu Su
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引用次数: 0

Abstract

The principle of structure dictating properties is illustrated by the direct correlation between cyclic peptide conformation and their biological efficacy. Plecanatide, a synthetic analogue of uroguanylin, has received FDA approval for the treatment of chronic idiopathic constipation (CIC) and irritable bowel syndrome with constipation (IBS-C). Nevertheless, our investigation has revealed that plecanatide undergoes slow conformational interconversion in slightly acidic conditions. In response, we strategically incorporated propargylglycine at the carboxyl terminal of plecanatide, a modification that not only facilitates additional functionalization and derivatization but also confers exceptional conformational stability. Remarkably, the resulting isomers not only maintained long-term conformational stability but also exhibited either preserved or slightly enhanced agonistic activity. This discovery represents a contribution to drug research focused on plecanatide, particularly in elucidating the relationship between its conformational properties and biological activity.

添加一个c端氨基酸可以阻止多聚糖类似物的构象相互转换。
结构决定性质的原理由环肽构象与其生物功效之间的直接关系来说明。Plecanatide是一种uroguananylin的合成类似物,已获得FDA批准用于治疗慢性特发性便秘(CIC)和肠易激综合征合并便秘(IBS-C)。然而,我们的研究表明,plecanatide在微酸性条件下经历缓慢的构象相互转化。作为回应,我们在plecanatide的羧基末端战略性地加入了丙基甘氨酸,这种修饰不仅促进了额外的官能化和衍生化,而且还赋予了特殊的构象稳定性。值得注意的是,所得到的异构体不仅保持了长期的构象稳定性,而且表现出保留或略微增强的激动活性。这一发现代表了对plecanatide药物研究的贡献,特别是在阐明其构象性质和生物活性之间的关系方面。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
ChemBioChem
ChemBioChem 生物-生化与分子生物学
CiteScore
6.10
自引率
3.10%
发文量
407
审稿时长
1 months
期刊介绍: ChemBioChem (Impact Factor 2018: 2.641) publishes important breakthroughs across all areas at the interface of chemistry and biology, including the fields of chemical biology, bioorganic chemistry, bioinorganic chemistry, synthetic biology, biocatalysis, bionanotechnology, and biomaterials. It is published on behalf of Chemistry Europe, an association of 16 European chemical societies, and supported by the Asian Chemical Editorial Society (ACES).
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