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首页> 外文期刊>European Journal of Medicinal Chemistry: Chimie Therapeutique >Rational design and biological evaluation of gemfibrozil modified Xenopus GLP-1 derivatives as long-acting hypoglycemic agents
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Rational design and biological evaluation of gemfibrozil modified Xenopus GLP-1 derivatives as long-acting hypoglycemic agents

机译：Gemfibrozil改性Xenopus GLP-1衍生物的理性设计与生物学评价为长效降血糖药物

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Novel methods for peptides structural modification and bioactivity optimization are highly needed in peptide-based drug discovery. Herein, we explored the use gemfibrozil (GFZ) as an albumin binder to enhance the stability and improve the bioactivity of peptides. Short-acting Xenopus glucagon-like peptide-1 (xGLP-1) analogues with anti-diabetic activity were selected as the starting point. Mono-GFZ conjugation, peptide sequence hybridization, and dimeric-GFZ derivatization were successively used to generate novel GFZ-xGLP-1 conjugates, biologically screened by various in vitro and in vivo models. Dimeric-GFZ modified conjugate 3b was finally identified as a promising anti-diabetic candidate with high albumin binding affinity, enhanced in vivo stability in SD rats, and long-acting hypoglycemic activity in db/db mice. Moreover, GFZ endowed 3b with strong lipid-regulating ability in DIO and db/db mice. In a twelve-week study, chronic administration of 3b in db/db mice resulted in sustained glycemic control, to a greater extent than liraglutide and semaglutide. In addition, 3b showed comparable therapeutic efficacies to liraglutide and semaglutide on HbA1c and pancreas islets protection. Our studies reveal 3b as a potential candidate for the treatment of metabolic diseases and indicate dimeric-GFZ modification as a novel method for peptide optimization. (C) 2020 Elsevier Masson SAS. All rights reserved.
机译：在基于肽的药物发现中，非常需要新的肽结构改性和生物活性优化方法。在此，我们探索了使用Gemfibrozil（GFZ）作为白蛋白粘合剂，以增强稳定性并改善肽的生物活性。选择具有抗糖尿病活性的短作用外爪血糖素样肽-1（XGLP-1）类似物作为起点。依次使用单可以-GFZ缀合，肽序列杂交和二聚体-GFZ衍生化，用于产生新的GFZ-XGLP-1缀合物，通过各种体外和体内模型进行生物学筛选。二聚体-GFZ改性缀合物3B最终鉴定为具有高白蛋白结合亲和力的有前途的抗糖尿病候选者，增强了SD大鼠的体内稳定性，以及DB / DB小鼠中的长效降血糖活性。此外，GFZ赋予3B，具有强大的DIO和DB / DB小鼠的脂质调节能力。在十二个一周的研究中，DB / DB小鼠中的3B慢性施用3B导致血糖控制持续血糖控制，比Liraglutide和Semaglutide更大。此外，3B显示出对HBA1C和胰岛胰岛保护的Liraglutide和Semagludere的类似治疗效果。我们的研究表明，3B作为治疗代谢疾病的潜在候选者，并表明二聚体-GFZ改性作为肽优化的新方法。 （c）2020 Elsevier Masson SAS。版权所有。

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