A piperidinyl indole derivative, potential complement factor B inhibitor, plays a renoprotective role in diabetic nephropathy

IF 3.4 3区医学 Q2 ENDOCRINOLOGY & METABOLISM

Diabetic Medicine Pub Date : 2025-06-15 DOI:10.1111/dme.70092

Zi-Han Li, Zi-Jun Sun, Dong-Yuan Chang, Ming-Hui Zhao, Sydney C. W. Tang, Min Chen

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引用次数: 0

Abstract

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.

查看原文本刊更多论文

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。

目的：糖尿病肾病（DN）是糖尿病（DM）最常见的并发症之一，也是世界范围内终末期肾病（ESKD）的主要原因。DN的发病机制是复杂的，越来越多的证据表明，补体系统的过度激活参与其中。补体因子B （CFB）是一种丝氨酸蛋白酶，驱动补体替代途径（AP）的中心扩增环，使其成为潜在的治疗靶点。在这项研究中，我们研究了胡椒酰吲哚衍生物对db/db小鼠的治疗潜力。方法：将高效靶向cfb的化合物(+)-4-(（2S,4R)-1-（（5-甲氧基-7-甲基- 1h -吲哚-4-基）甲基）-4-甲基哌啶-2-基）苯甲酸（以下简称“化合物”）口服于db/db小鼠模型。应用生物信息学和网络药理学分析方法进行研究。结果：口服该化合物可减轻db/db小鼠的DN，其表现为尿白蛋白与肌酸比（uACR）降低、小管间质炎症和纤维化以及肾小球基底膜增厚。生物信息学和网络药理学分析表明，该化合物除了能结合CFB酶切活化片段Bb的活性位点，抑制AP补体成分3 （C3）转化酶的活性外，还能调节肾小管凋亡的关键执行因子——半胱氨酸天冬氨酸特异性蛋白酶3 （CASP3）和肾小管间质促纤维化驱动因子——二肽基肽酶4 （DPP4）的表达。这些互补机制共同抑制了补体的过度激活和细胞凋亡/纤维化级联，共同缓解了DN的进展。结论：我们的数据揭示了哌啶基吲哚衍生物治疗DN的潜在治疗策略，为其临床开发提供了依据。

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

Diabetic Medicine 医学-内分泌学与代谢

CiteScore

7.20

自引率

5.70%

发文量

229

审稿时长

3-6 weeks

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.”