伪不可逆抑制引发鞘氨醇1-磷酸受体1拮抗剂的持续疗效-动脉网

Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist

Nature 等信源发布 2024-07-19 18:56

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AbstractSphingosine 1-phosphate receptor 1 (S1PR1), a G protein-coupled receptor, is required for lymphocyte trafficking, and is a promising therapeutic target in inflammatory diseases. Here, we synthesize a competitive S1PR1 antagonist, KSI-6666, that effectively suppresses pathogenic inflammation.

摘要鞘氨醇1-磷酸受体1（S1PR1）是一种G蛋白偶联受体，是淋巴细胞运输所必需的，是炎症性疾病的有希望的治疗靶点。在这里，我们合成了一种竞争性S1PR1拮抗剂KSI-6666，可有效抑制致病性炎症。

Metadynamics simulations suggest that the interaction of KSI-6666 with a methionine residue Met124 in the ligand-binding pocket of S1PR1 may inhibit the dissociation of KSI-6666 from S1PR1. Consistently, in vitro functional and mutational analyses reveal that KSI-6666 causes pseudoirreversible inhibition of S1PR1, dependent on the Met124 of the protein and substituents on the distal benzene ring of KSI-6666.

元动力学模拟表明，KSI-6666与S1PR1配体结合口袋中蛋氨酸残基Met124的相互作用可能会抑制KSI-6666与S1PR1的解离。一致地，体外功能和突变分析表明，KSI-6666引起S1PR1的假不可逆抑制，这取决于蛋白质的Met124和KSI-6666远端苯环上的取代基。

Moreover, in vivo study suggests that this pseudoirreversible inhibition is responsible for the persistent activity of KSI-6666..

此外，体内研究表明，这种假不可逆抑制是KSI-6666持续活性的原因。。

IntroductionSphingosine 1-phosphate (S1P), which is a metabolite of membrane sphingolipids, regulates cell migration, inflammatory response, angiogenesis, and neurogenesis1. The physiological functions of S1P are mediated by its binding to five subtypes of the sphingosine 1-phosphate receptor, which belongs to the G protein-coupled receptor (GPCR) family1.

简介鞘氨醇1-磷酸（S1P）是膜鞘脂的代谢产物，可调节细胞迁移，炎症反应，血管生成和神经发生1。S1P的生理功能是通过其与属于G蛋白偶联受体（GPCR）家族1的鞘氨醇1-磷酸受体的五种亚型的结合来介导的。

Among S1P receptors (S1PRs), S1P receptor 1 (S1PR1) is critical for lymphocyte trafficking and progression of immune and inflammatory responses. The binding of S1P to S1PR1 causes activation of Gi, a subunit of heterotrimeric guanine nucleotide-binding proteins (G proteins), leading to the inhibition of adenylate cyclase-induced cAMP synthesis and subsequent activation of several intracellular signaling pathways.

在S1P受体（S1PR）中，S1P受体1（S1PR1）对于淋巴细胞运输以及免疫和炎症反应的进展至关重要。S1P与S1PR1的结合导致Gi（异源三聚体鸟嘌呤核苷酸结合蛋白（G蛋白）的亚基）的激活，从而抑制腺苷酸环化酶诱导的cAMP合成并随后激活几种细胞内信号传导途径。

The binding also induces the phosphorylation-dependent recruitment of β-arrestin and subsequent cellular internalization of the ligand–receptor complex.Given its roles in lymphocyte trafficking, S1PR1 is a target for the treatment of autoimmune and inflammatory diseases. FTY720, also named fingolimod, is a first-generation S1PR1 modulator that was approved as a drug for the treatment of multiple sclerosis (MS)2,3.

这种结合还诱导β-抑制蛋白的磷酸化依赖性募集以及随后配体-受体复合物的细胞内化。鉴于其在淋巴细胞运输中的作用，S1PR1是治疗自身免疫性和炎性疾病的靶标。FTY720，也称为芬戈莫德，是第一代S1PR1调节剂，被批准作为治疗多发性硬化症（MS）的药物2,3。

Mechanistically, FTY720 is phosphorylated in vivo into FTY720-phosphate (FTY720-P), which serves as a functional antagonist of S1PRs including S1PR12. Thus, the binding of FTY720-P activates S1PR1 signaling, leading to the internalization and subsequent degradation of S1PR1. As a result, administration of FTY720 causes long-lasting inhibition of S1PR1 signaling through the depletion of cell surface S1PR1.

从机理上讲，FTY720在体内被磷酸化为FTY720磷酸盐（FTY720-P），FTY720-P可作为S1PR（包括S1PR12）的功能性拮抗剂。因此，FTY720-P的结合激活S1PR1信号传导，导致S1PR1的内在化和随后的降解。结果，FTY720的施用通过细胞表面S1PR1的消耗引起S1PR1信号传导的持久抑制。

However, in addition to lymphocyte trafficking, S1PR1 controls the function of cardiac cells4. Therefore, the agonistic activity of FTY720-P provokes bradycardia4,5,6, a temporal reduction of the h.

然而，除了淋巴细胞运输外，S1PR1还控制心脏细胞的功能4。因此，FTY720-P的激动活性引起心动过缓4,5,6，即h的时间减少。

Data availability

数据可用性

Source data are provided within this paper. The MD simulation data including input files and final output configurations have been deposited to GitHub depository, https://github.com/CHEMINFO-tsukuba/Nat.Comm.2024.git. Photo image data generated in the current study are available in the Zenodo database, https://doi.org/10.5281/zenodo.11260928. Source data are provided with this paper..

本文提供了源数据。MD模拟数据（包括输入文件和最终输出配置）已保存到GitHub depository，https://github.com/CHEMINFO-tsukuba/Nat.Comm.2024.git.Zenodo数据库中提供了当前研究中生成的照片图像数据，https://doi.org/10.5281/zenodo.11260928.本文提供了源数据。。

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and N.A.), Grants-in-Aid for Scientific Research in Innovative Areas from MEXT (18H04989 and 19H04821 to T.A. and N.A.) and by CREST from the Japan Science and Technology Agency (JPMJCR2011 to T.A.). We thank Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.Author informationAuthors and AffiliationsLaboratory for Immune Homeostasis, RIKEN Center for Integrative Medical Sciences, Yokohama, 230-0045, JapanYuya Maruyama, Wataru Muramatsu, Kano Namiki, Naho Hagiwara, Maki Miyauchi, Takahisa Miyao, Tatsuya Ishikawa, Kenta Horie, Mio Hayama, Nobuko Akiyama & Taishin AkiyamaImmunobiology, Graduate School of Medical Life Science, Yokohama City University, Yokohama, 230-0045, JapanYuya Maruyama, Wataru Muramatsu, Kano Namiki, Maki Miyauchi, Tatsuya Ishikawa, Mio Hayama, Nobuko Akiyama & Taishin AkiyamaCentral Research Laboratory, Kissei Pharmaceutical Co., Ltd., 4365-1 Hotaka-Kashiwabara, Azumino, Nagano, 399-8304, JapanYuya Maruyama, Yusuke Ohsawa, Takayuki Suzuki, Yuko Yamauchi, Kohsuke Ohno, Hitoshi Inoue, Akitoshi Yamamoto, Morimichi Hayashi & Yuji OkuharaDivision of Biomedical Science, Faculty of Medicine, University of Tsukuba, 1-1-1 Tennodai, Tsukuba, Ibaraki, 305-8575, JapanTakatsugu HirokawaTransborder Medical Research Center, Univ.

和N.A.），MEXT（18H04989和19H04821授予T.A.和N.A.）和CREST（日本科学技术厅（JPMJCR2011授予T.A.）的创新领域科学研究补助金。我们感谢Edanz(https://jp.edanz.com/ac)编辑这份手稿的草稿。作者信息作者和附属机构免疫稳态实验室，日本理研综合医学科学中心，横滨，230-0045，日本丸山，村松渡，Kano Namiki，Naho Hagiwara，Maki Miyauchi，Miyao Tatsuya Ishikawa，Kenta Horie，Mio Hayama，Nobuko Akiyama和Taishin AkiyamaImmunobiology，横滨城市大学医学生命科学研究生院，横滨，230-0045，日本丸山渡，村松渡，Kano Namiki，Maki Miyama内町，石川达也，宫山弥生，秋山信子和秋山太新中央研究实验室，基西制药有限公司，4365-1和田，长野阿祖米诺，399-8304，日本丸山，大泽佑介，铃木，山内幸子，大野广介，井上春树，山本明敏，林下和冈原裕二筑波大学医学院生物医学科学系，筑波田纳西1-1-1茨城县，305-8575，日本广川县医学研究中心，大学。

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PubMed Google ScholarContributionsY.M., Y. Ohsawa, T.S., M.M., T.M., N.A., W.M., K.N. and N.H. performed the experiments. K.O. and H.I. synthesized the chemicals. A.Y. performed LC-MS analysis. M.H. and Y. Okuhara performed histological analysis. Y.Y. and T.H. performed in silico calculations.

PubMed谷歌学术贡献。M、，Y.Ohsawa，T.S.，M.M.，T.M.，N.A.，W.M.，K.N.和N.H.进行了实验。K、 O.和H.I.合成了这些化学品。A、 Y.进行LC-MS分析。M、 H.和Y.Okuhara进行了组织学分析。Y、 Y.和T.H.进行了计算机计算。

Y.M., Y.Y., T.I., K.H., M.H., T.H. and T.A. analyzed the MetaD data. Y.M. and T.A. designed the study and wrote the paper.Corresponding authorCorrespondence to.

Y、 M.，Y.Y.，T.I.，K.H.，M.H.，T.H.和T.A.分析了MetaD数据。Y、 M.和T.A.设计了这项研究并撰写了论文。对应作者对应。

Taishin Akiyama.Ethics declarations

Taishin Akiyama。道德宣言

Competing interests

相互竞争的利益

YM, Y. Ohsawa, TS, YY, KO, HI, AY, MH, and Y. Okuhara are employees of Kissei Pharmaceutical Co., Ltd. and may hold stock in the company. The remaining authors declare no competing interests.

YM、Y.Ohsawa、TS、YY、KO、HI、AY、MH和Y.Okuhara是Kissei Pharmaceutical Co.，Ltd.的员工，可能持有公司股票。其余作者声明没有利益冲突。

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Reprints and permissionsAbout this articleCite this articleMaruyama, Y., Ohsawa, Y., Suzuki, T. et al. Pseudoirreversible inhibition elicits persistent efficacy of a sphingosine 1-phosphate receptor 1 antagonist.

转载和许可本文引用本文Maruyama，Y.，Ohsawa，Y.，Suzuki，T。等人。假不可逆抑制引起鞘氨醇1-磷酸受体1拮抗剂的持续功效。

Nat Commun 15, 5743 (2024). https://doi.org/10.1038/s41467-024-49893-8Download citationReceived: 18 April 2023Accepted: 19 June 2024Published: 19 July 2024DOI: https://doi.org/10.1038/s41467-024-49893-8Share this articleAnyone you share the following link with will be able to read this content:Get shareable linkSorry, a shareable link is not currently available for this article.Copy to clipboard.

《国家公社》155743（2024）。https://doi.org/10.1038/s41467-024-49893-8Download引文接收日期：2023年4月18日接收日期：2024年6月19日发布日期：2024年7月19日OI：https://doi.org/10.1038/s41467-024-49893-8Share本文与您共享以下链接的任何人都可以阅读此内容：获取可共享链接对不起，本文目前没有可共享的链接。复制到剪贴板。

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