Minimalist d-Tripeptide Prodrug Mimetics of the Myostatin Prodomain as Selective Inhibitors of Skeletal Muscle Atrophy Signaling

IF 3.9 3区医学 Q2 CHEMISTRY, MEDICINAL

ACS Medicinal Chemistry Letters Pub Date : 2026-10-08 Epub Date: 2026-09-04 DOI:10.1021/acsmedchemlett.6c00358

Jae Ho Shim, Ji Yeon Lee, Jihye Han, Hyeon Soo Kim

引用次数: 0

Abstract

Skeletal muscle atrophy is driven in part by unrestrained myostatin (MSTN) signaling. We designed all-d tripeptide prodrug mimetics of the MSTN prodomain minimum active 23-mer fragment. Compounds 1 (H-d-Arg-d-Leu-d-Ala-OiPr) and 2 (H-d-Arg-d-Abu-d-Ala-OiPr) inhibited MSTN-induced myotube atrophy with sub-micromolar potency, while free-acid analogues (3, 4) and scrambled control (scr) were less active. All-d configuration conferred proteolytic stability exceeding 24 h. In vivo, compound 1 increased soleus mass and grip strength in mice. This work establishes compound 1 as a lead prodrug for MSTN antagonism in muscle atrophy.

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肌生长抑制素前域的极简d-三肽前药模拟物作为骨骼肌萎缩信号传导的选择性抑制剂

骨骼肌萎缩部分是由不受抑制的肌生长抑制素（MSTN）信号驱动的。我们设计了MSTN前域最小活性23-mer片段的全d三肽前药模拟物。化合物1 （H-d-Arg-d-Leu-d-Ala-OiPr）和2 （H-d-Arg-d-Abu-d-Ala-OiPr）以亚微摩尔效价抑制mstn诱导的肌管萎缩，而游离酸类似物（3,4）和混乱对照（scr）的活性较低。在体内，化合物1增加了小鼠比目鱼的质量和握力。这项工作确立了化合物1作为肌萎缩症MSTN拮抗的主要前药。

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

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.