{"title":"通过冷冻电镜分析优化α-氨基硼酸:发现新型高选择性免疫蛋白酶体亚基 LMP7 (β5i)/LMP2 (β1i) 双抑制剂","authors":"Yuuki Arai , Hiroaki Shitama , Masahito Yamagishi , Satoshi Ono , Akiko Kashima , Masahiro Hiraizumi , Naoki Tsuda , Koushirou Katayama , Kouji Tanaka , Yuzo Koda , Sayuka Kato , Kei Sakata , Osamu Nureki , Hiroshi Miyazaki","doi":"10.1016/j.bmc.2024.117790","DOIUrl":null,"url":null,"abstract":"<div><p>The immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit β5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over β5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor <strong>19</strong>. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with <strong>19</strong> explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that <strong>19</strong> is orally bioavailable and shows promise as potential treatment for autoimmune diseases.</p></div>","PeriodicalId":255,"journal":{"name":"Bioorganic & Medicinal Chemistry","volume":null,"pages":null},"PeriodicalIF":3.3000,"publicationDate":"2024-06-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Optimization of α-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual inhibitor\",\"authors\":\"Yuuki Arai , Hiroaki Shitama , Masahito Yamagishi , Satoshi Ono , Akiko Kashima , Masahiro Hiraizumi , Naoki Tsuda , Koushirou Katayama , Kouji Tanaka , Yuzo Koda , Sayuka Kato , Kei Sakata , Osamu Nureki , Hiroshi Miyazaki\",\"doi\":\"10.1016/j.bmc.2024.117790\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><p>The immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit β5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over β5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor <strong>19</strong>. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with <strong>19</strong> explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that <strong>19</strong> is orally bioavailable and shows promise as potential treatment for autoimmune diseases.</p></div>\",\"PeriodicalId\":255,\"journal\":{\"name\":\"Bioorganic & Medicinal Chemistry\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":3.3000,\"publicationDate\":\"2024-06-12\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Bioorganic & Medicinal Chemistry\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S0968089624002049\",\"RegionNum\":3,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q2\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Bioorganic & Medicinal Chemistry","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S0968089624002049","RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q2","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
据报道,免疫蛋白酶体亚基 LMP7(β5i)/LMP2(β1i)双重阻断可抑制 B 细胞分化和活化,这表明 LMP7/LMP2 双重抑制是治疗自身免疫性疾病的一种很有前景的方法。相反,组成型蛋白酶体亚基β5c的抑制作用与对非免疫细胞的细胞毒性相关。因此,对β5c具有高选择性的LMP7/LMP2双重抑制剂可能是治疗自身免疫性疾病的理想选择。在本研究中,我们利用冷冻电子显微镜(cryo-EM)对α-氨基硼酸进行了优化和发现。利用蛋白酶体亚基之间的结构差异,我们发现了一种高选择性的 LMP7/LMP2 双抑制剂 19。基于蛋白酶体亚基与 19 复合物的低温电子显微镜结构的分子动力学模拟解释了抑制活性概况。在用 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin 对小鼠进行免疫后,结果表明 19 具有口服生物利用度,有望成为治疗自身免疫性疾病的潜在药物。
Optimization of α-amido boronic acids via cryo-electron microscopy analysis: Discovery of a novel highly selective immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual inhibitor
The immunoproteasome subunit LMP7 (β5i)/LMP2 (β1i) dual blockade has been reported to suppress B cell differentiation and activation, suggesting that the dual inhibition of LMP7/LMP2 is a promising approach for treating autoimmune diseases. In contrast, the inhibition of the constitutive proteasome subunit β5c correlates with cytotoxicity against non-immune cells. Therefore, LMP7/LMP2 dual inhibitors with high selectivity over β5c may be desirable for treating autoimmune diseases. In this study, we present the optimization and discovery of α-amido boronic acids using cryo-electron microscopy (cryo-EM). The exploitation of structural differences between the proteasome subunits led to the identification of a highly selective LMP7/LMP2 dual inhibitor 19. Molecular dynamics simulation based on cryo-EM structures of the proteasome subunits complexed with 19 explained the inhibitory activity profile. In mice immunized with 4-hydroxy-3-nitrophenylacetyl conjugated to ovalbumin, results indicate that 19 is orally bioavailable and shows promise as potential treatment for autoimmune diseases.
期刊介绍:
Bioorganic & Medicinal Chemistry provides an international forum for the publication of full original research papers and critical reviews on molecular interactions in key biological targets such as receptors, channels, enzymes, nucleotides, lipids and saccharides.
The aim of the journal is to promote a better understanding at the molecular level of life processes, and living organisms, as well as the interaction of these with chemical agents. A special feature will be that colour illustrations will be reproduced at no charge to the author, provided that the Editor agrees that colour is essential to the information content of the illustration in question.