通过丙氨酸扫描对抗击破骨细胞分化的 FRATtide 基因进行系统突变分析

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2024-07-10 DOI:10.1021/acsmedchemlett.4c0012710.1021/acsmedchemlett.4c00127

Yi Yang, Chenchen Geng, Huaxing Shen, Jingru Chao, Zhe Wang, Wei Cong, Xiang Li*, Guangming Ye* and Yunyun Jiang*,

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引用次数: 0

摘要

骨质疏松症是一种全球性骨病，会导致骨密度、骨量减少和微结构退化，增加骨折风险。在以前的研究中，FRATtide 是一种从糖原合酶激酶-3 结合蛋白中提取的多肽，它能有效阻碍破骨细胞的分化，通过单钉和双钉产生具有治疗效果的衍生物。然而，FRATtide 的结构-活性关系仍不清楚。本研究通过系统的丙氨酸扫描合成了 25 种 FRATtide 衍生肽，并评估了它们的活性。Pro2、Leu5、Leu9、Val10、Leu11、Ser12、Asn14、Leu15、Ile16、Glu18、Arg22、Ser25 和 Arg26 的取代显示出活性降低，而分别取代 Gly13 和 Arg21 的 FRT13 和 FRT20 则显示出活性增强。与 FRATtide 相比，FRT13 和 FRT20 的 F-肌动蛋白结合和骨吸收试验表明，它们能更好地抑制破骨细胞分化和骨吸收。这项研究阐明了 FRATtide 的结构-活性关系，从而促进了未来骨质疏松症治疗的结构优化。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

Systematical Mutational Analysis of FRATtide against Osteoclast Differentiation by Alanine Scanning

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Systematical Mutational Analysis of FRATtide against Osteoclast Differentiation by Alanine Scanning

Osteoporosis, a global bone disease, results in decreased bone density, mass, and microarchitecture deterioration, increasing fracture risk. In previous research, FRATtide, a peptide derived from a glycogen synthase kinase-3 binding protein, effectively hindered osteoclast differentiation to yield therapeutically potent derivatives via single and double stapling. However, FRATtide’s structure–activity relationship remains unclear. This study synthesized 25 FRATtide-derived peptides through systematic alanine scanning and evaluated their activities. Substitutions in Pro², Leu⁵, Leu⁹, Val¹⁰, Leu¹¹, Ser^12, Asn¹⁴, Leu¹⁵, Ile¹⁶, Glu¹⁸, Arg²², Ser²⁵, and Arg²⁶ showed reduced activity, while FRT13 and FRT20 with Gly¹³ and Arg²¹ substitutions, respectively, displayed enhanced activities. F-actin binding and bone resorption assays on FRT13 and FRT20 showed better inhibition of osteoclast differentiation and bone resorption compared with FRATtide. This study elucidated FRATtide’s structure–activity relationship, thereby facilitating future structural optimization for osteoporosis treatment.

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.