Yuanqi Lin, Hiroaki Itoh, Shingo Dan, Masayuki Inoue
{"title":"Methyl Scanning Approach for Enhancing the Biological Activity of the Linear Peptidic Natural Product, Efrapeptin C","authors":"Yuanqi Lin, Hiroaki Itoh, Shingo Dan, Masayuki Inoue","doi":"10.1039/d4sc04384g","DOIUrl":null,"url":null,"abstract":"Efrapeptin C (<strong>1a</strong>) is a large peptidic natural product comprising a 15-mer linear sequence and exerts potent anticancer activity by inhibiting mitochondrial F<small><sub>o</sub></small>F<small><sub>1</sub></small>-ATP synthase. Residues 1–6 and 9–15 of <strong>1a</strong> fold into two 3<small><sub>10</sub></small>-helical domains and interact with ATP synthase, while the central β-Ala-7–Gly-8 region functions as a flexible linker of the two domains. To enhance the function of <strong>1a</strong> by minimally modifying its structure, we envisioned attaching one small methyl group to the β-Ala-7–Gly-8 and designed six methylated analogues <strong>1b</strong>–<strong>1g</strong>, differing only in the position and configuration of the methyl group. We enabled the first solid-phase total synthesis of <strong>1a</strong> and unified syntheses of <strong>1b</strong>–<strong>1g</strong>. The growth inhibitory activities of <strong>1a</strong>–<strong>1g</strong> against MCF-7 cells varied significantly: <strong>1f</strong> with (<em>S</em>)-β<small><sup>3</sup></small>-hAla-7 and its epimer <strong>1g</strong> with (<em>R</em>)-β<small><sup>3</sup></small>-hAla-7 were 4-fold more and 5-fold less potent, respectively, than <strong>1a</strong>. Remarkably, the most potent <strong>1f</strong> had the most stabilized 3<small><sub>10</sub></small>-helical conformation and the highest hydrophobicity, which likely contributed to its effective transfer to the target protein within mitochondria. Moreover, <strong>1f</strong> exhibited higher proteolytic stability than <strong>1a</strong>. Therefore, the present methyl scanning approach provides a new strategy for changing the original properties of linear peptidic natural products to develop new pharmaceuticals.","PeriodicalId":9909,"journal":{"name":"Chemical Science","volume":null,"pages":null},"PeriodicalIF":7.6000,"publicationDate":"2024-10-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Chemical Science","FirstCategoryId":"92","ListUrlMain":"https://doi.org/10.1039/d4sc04384g","RegionNum":1,"RegionCategory":"化学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"CHEMISTRY, MULTIDISCIPLINARY","Score":null,"Total":0}
引用次数: 0
Abstract
Efrapeptin C (1a) is a large peptidic natural product comprising a 15-mer linear sequence and exerts potent anticancer activity by inhibiting mitochondrial FoF1-ATP synthase. Residues 1–6 and 9–15 of 1a fold into two 310-helical domains and interact with ATP synthase, while the central β-Ala-7–Gly-8 region functions as a flexible linker of the two domains. To enhance the function of 1a by minimally modifying its structure, we envisioned attaching one small methyl group to the β-Ala-7–Gly-8 and designed six methylated analogues 1b–1g, differing only in the position and configuration of the methyl group. We enabled the first solid-phase total synthesis of 1a and unified syntheses of 1b–1g. The growth inhibitory activities of 1a–1g against MCF-7 cells varied significantly: 1f with (S)-β3-hAla-7 and its epimer 1g with (R)-β3-hAla-7 were 4-fold more and 5-fold less potent, respectively, than 1a. Remarkably, the most potent 1f had the most stabilized 310-helical conformation and the highest hydrophobicity, which likely contributed to its effective transfer to the target protein within mitochondria. Moreover, 1f exhibited higher proteolytic stability than 1a. Therefore, the present methyl scanning approach provides a new strategy for changing the original properties of linear peptidic natural products to develop new pharmaceuticals.
期刊介绍:
Chemical Science is a journal that encompasses various disciplines within the chemical sciences. Its scope includes publishing ground-breaking research with significant implications for its respective field, as well as appealing to a wider audience in related areas. To be considered for publication, articles must showcase innovative and original advances in their field of study and be presented in a manner that is understandable to scientists from diverse backgrounds. However, the journal generally does not publish highly specialized research.