Diabetes mellitus drug discovery: insights into targeting feline and human amylin with small molecules.

IF 7.9 2区 农林科学 Q1 VETERINARY SCIENCES
Veterinary Quarterly Pub Date : 2023-12-01 Epub Date: 2023-10-04 DOI:10.1080/01652176.2023.2260442
Kendall B E Moore, Natalie G Horgan, Brooke Lenters, Jessica S Fortin
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引用次数: 0

Abstract

Background: Type 2 diabetes (T2D) is a health concern for both humans and cats, with cases rising over the past decade. Around 70% of patients from either species exhibit pancreatic aggregates of islet amyloid polypeptide (IAPP), a protein that proves toxic upon misfolding. These misfolded protein aggregates congregate in the islets of Langerhans of the pancreas, diminishing the capability of β-cells to produce insulin and further perpetuating disease.

Objective: Our team's drug discovery program is investigating newly synthesized compounds that could diminish aggregates of both human and feline IAPP, potentially disrupting the progression of T2D.

Material and methods: We prepared 24 compounds derived from diaryl urea, as ureas have previously demonstrated great potential at reducing accumulations of misfolded proteins. Biophysical methods were employed to analyze the anti-aggregation activity of these compounds at inhibiting and/or disrupting IAPP fibril formation in vitro.

Results: The results demonstrate that compounds 12 and 24 were most effective at reducing the fibrillization and aggregation of both human and feline IAPP. When compared with the control for each experiment, samples treated with either compound 12 or 24 exhibited fewer accumulations of amyloid-like fibrils.

Conclusion: Urea-based compounds, such as compounds 12 and 24, may prove crucial in future pre-clinical studies in the search for therapeutics for T2D.

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糖尿病药物发现:用小分子靶向猫和人胰淀素的见解。
背景:2型糖尿病(T2D)是人类和猫的健康问题,在过去十年中,病例不断增加。来自这两个物种的大约70%的患者表现出胰岛淀粉样多肽(IAPP)的胰腺聚集体,这种蛋白质在错误折叠时被证明是有毒的。这些错误折叠的蛋白质聚集体聚集在胰腺的朗格汉斯胰岛中,降低了β细胞产生胰岛素的能力,并进一步使疾病永久化。目的:我们团队的药物发现项目正在研究新合成的化合物,这些化合物可以减少人类和猫IAPP的聚集体,可能会破坏T2D的进展。材料和方法:我们制备了24种来源于二芳基脲的化合物,因为脲在减少错误折叠蛋白质的积累方面具有巨大潜力。采用生物物理方法分析了这些化合物在体外抑制和/或破坏IAPP原纤维形成方面的抗聚集活性。结果:化合物12和24对减少人和猫IAPP的原纤维化和聚集最有效。当与每个实验的对照相比时,用化合物12或24处理的样品表现出较少的淀粉样原纤维的积聚。结论:尿素基化合物,如化合物12和24,可能在未来寻找T2D治疗方法的临床前研究中至关重要。
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来源期刊
Veterinary Quarterly
Veterinary Quarterly VETERINARY SCIENCES-
CiteScore
13.10
自引率
1.60%
发文量
18
审稿时长
>24 weeks
期刊介绍: Veterinary Quarterly is an international open access journal which publishes high quality review articles and original research in the field of veterinary science and animal diseases. The journal publishes research on a range of different animal species and topics including: - Economically important species such as domesticated and non-domesticated farm animals, including avian and poultry diseases; - Companion animals (dogs, cats, horses, pocket pets and exotics); - Wildlife species; - Infectious diseases; - Diagnosis; - Treatment including pharmacology and vaccination
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