Zi-Han Li, Zi-Jun Sun, Dong-Yuan Chang, Ming-Hui Zhao, Sydney C. W. Tang, Min Chen
{"title":"一种哌啶基吲哚衍生物，潜在的补体因子B抑制剂，在糖尿病肾病中起着保护肾的作用。","authors":"Zi-Han Li, Zi-Jun Sun, Dong-Yuan Chang, Ming-Hui Zhao, Sydney C. W. Tang, Min Chen","doi":"10.1111/dme.70092","DOIUrl":null,"url":null,"abstract":"<div>\n \n \n <section>\n \n <h3> Aims</h3>\n \n <p>Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM) and the main cause of end-stage kidney disease (ESKD) worldwide. The pathogenesis of DN is complex, and cumulating evidence demonstrated that over-activation of the complement system is involved. Complement factor B (CFB), a serine protease, drives the central amplification loop of the alternative pathway (AP) of the complement, making it a potential therapeutic target. In this study, we investigated the therapeutic potential of a piperidinyl indole derivative in <i>db</i>/<i>db</i> mice.</p>\n </section>\n \n <section>\n \n <h3> Methods</h3>\n \n <p>A highly potent CFB-targeting compound, (+)-4-((2<i>S</i>,4<i>R</i>)-1-((5-methoxy-7-methyl-1<i>H</i>-indol-4-yl) methyl)-4-methylpiperidin-2-yl) benzoic acid (hereafter referred as the “compound”), was orally administered to the <i>db</i>/<i>db</i> mice model. Bioinformatics and network pharmacology analyses were applied in our research.</p>\n </section>\n \n <section>\n \n <h3> Results</h3>\n \n <p>Oral administration of the compound attenuated established DN in <i>db</i>/<i>db</i> mice, as evidenced by reduced urine albumin-to-creatine ratio (uACR), tubulointerstitial inflammation and fibrosis, and thickening of glomerular basement membrane. Besides binding to the active site of Bb, the enzyme-cleaved activated fragment of CFB, and inhibiting the activity of complement component 3 (C3) convertase of the AP, the compound could regulate the expression of cysteinyl aspartate specific proteinase 3 (CASP3, a key executor of renal tubular apoptosis) and dipeptidyl peptidase 4 (DPP4, a pro-fibrotic driver in tubulointerstitium) by bioinformatics and network pharmacology analysis. These complementary mechanisms cooperated to inhibit the over-activation of complements and the apoptosis/fibrosis cascade and together alleviated DN progression.</p>\n </section>\n \n <section>\n \n <h3> Conclusions</h3>\n \n <p>Our data revealed the potential therapeutic strategy of using the piperidinyl indole derivative for the treatment of DN and provided a basis for its clinical development.</p>\n </section>\n </div>","PeriodicalId":11251,"journal":{"name":"Diabetic Medicine","volume":"42 8","pages":""},"PeriodicalIF":3.4000,"publicationDate":"2025-06-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A piperidinyl indole derivative, potential complement factor B inhibitor, plays a renoprotective role in diabetic nephropathy\",\"authors\":\"Zi-Han Li, Zi-Jun Sun, Dong-Yuan Chang, Ming-Hui Zhao, Sydney C. W. Tang, Min Chen\",\"doi\":\"10.1111/dme.70092\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div>\\n \\n \\n <section>\\n \\n <h3> Aims</h3>\\n \\n <p>Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM) and the main cause of end-stage kidney disease (ESKD) worldwide. The pathogenesis of DN is complex, and cumulating evidence demonstrated that over-activation of the complement system is involved. Complement factor B (CFB), a serine protease, drives the central amplification loop of the alternative pathway (AP) of the complement, making it a potential therapeutic target. In this study, we investigated the therapeutic potential of a piperidinyl indole derivative in <i>db</i>/<i>db</i> mice.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Methods</h3>\\n \\n <p>A highly potent CFB-targeting compound, (+)-4-((2<i>S</i>,4<i>R</i>)-1-((5-methoxy-7-methyl-1<i>H</i>-indol-4-yl) methyl)-4-methylpiperidin-2-yl) benzoic acid (hereafter referred as the “compound”), was orally administered to the <i>db</i>/<i>db</i> mice model. Bioinformatics and network pharmacology analyses were applied in our research.</p>\\n </section>\\n \\n <section>\\n \\n <h3> Results</h3>\\n \\n <p>Oral administration of the compound attenuated established DN in <i>db</i>/<i>db</i> mice, as evidenced by reduced urine albumin-to-creatine ratio (uACR), tubulointerstitial inflammation and fibrosis, and thickening of glomerular basement membrane. 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A piperidinyl indole derivative, potential complement factor B inhibitor, plays a renoprotective role in diabetic nephropathy
Aims
Diabetic nephropathy (DN) is one of the most common complications of diabetes mellitus (DM) and the main cause of end-stage kidney disease (ESKD) worldwide. The pathogenesis of DN is complex, and cumulating evidence demonstrated that over-activation of the complement system is involved. Complement factor B (CFB), a serine protease, drives the central amplification loop of the alternative pathway (AP) of the complement, making it a potential therapeutic target. In this study, we investigated the therapeutic potential of a piperidinyl indole derivative in db/db mice.
Methods
A highly potent CFB-targeting compound, (+)-4-((2S,4R)-1-((5-methoxy-7-methyl-1H-indol-4-yl) methyl)-4-methylpiperidin-2-yl) benzoic acid (hereafter referred as the “compound”), was orally administered to the db/db mice model. Bioinformatics and network pharmacology analyses were applied in our research.
Results
Oral administration of the compound attenuated established DN in db/db mice, as evidenced by reduced urine albumin-to-creatine ratio (uACR), tubulointerstitial inflammation and fibrosis, and thickening of glomerular basement membrane. Besides binding to the active site of Bb, the enzyme-cleaved activated fragment of CFB, and inhibiting the activity of complement component 3 (C3) convertase of the AP, the compound could regulate the expression of cysteinyl aspartate specific proteinase 3 (CASP3, a key executor of renal tubular apoptosis) and dipeptidyl peptidase 4 (DPP4, a pro-fibrotic driver in tubulointerstitium) by bioinformatics and network pharmacology analysis. These complementary mechanisms cooperated to inhibit the over-activation of complements and the apoptosis/fibrosis cascade and together alleviated DN progression.
Conclusions
Our data revealed the potential therapeutic strategy of using the piperidinyl indole derivative for the treatment of DN and provided a basis for its clinical development.
期刊介绍：
Diabetic Medicine, the official journal of Diabetes UK, is published monthly simultaneously, in print and online editions.
The journal publishes a range of key information on all clinical aspects of diabetes mellitus, ranging from human genetic studies through clinical physiology and trials to diabetes epidemiology. We do not publish original animal or cell culture studies unless they are part of a study of clinical diabetes involving humans. Categories of publication include research articles, reviews, editorials, commentaries, and correspondence. All material is peer-reviewed.
We aim to disseminate knowledge about diabetes research with the goal of improving the management of people with diabetes. The journal therefore seeks to provide a forum for the exchange of ideas between clinicians and researchers worldwide. Topics covered are of importance to all healthcare professionals working with people with diabetes, whether in primary care or specialist services.
Surplus generated from the sale of Diabetic Medicine is used by Diabetes UK to know diabetes better and fight diabetes more effectively on behalf of all people affected by and at risk of diabetes as well as their families and carers.”
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