Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems.
Discovery of a potent GIPR peptide antagonist that is effective in rodent and human systems.
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DOI：
10.1016/j.molmet.2022.101638
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发表时间：
2022-12
影响因子：
8.1
通讯作者：
Finan, Brian
中科院分区：
文献类型：
--
作者：
Yang, Bin;Gelfanov, Vasily M.;El, Kimberley;Chen, Alex;Rohlfs, Rebecca;DuBois, Barent;Hansen, Ann Maria Kruse;Perez-Tilve, Diego;Knerr, Patrick J.;'Alessio, David;Campbell, Jonathan E.;Douros, Jonathan D.;Finan, Brian
葡萄糖依赖性促胰岛素多肽（GIP）是调节代谢稳态的两种主要肠促胰岛素因子之一。在小鼠中，其受体（GIPR）的基因消融可保护小鼠免受饮食诱导的肥胖（DIO），而在临床前模型和临床试验中，GIPR中和抗体与GLP-1 R激动剂联合使用时可产生额外的体重减轻。相反，GIPR激动剂已被证明可促进啮齿类动物的体重减轻，而GLP-1 R/GIPR双重激动剂在临床试验中证明上级GLP-1 R单激动剂。我们试图开发一种长效的，特异性的GIPR肽拮抗剂作为工具化合物，适用于研究啮齿动物和人类系统中的GIPR药理学。我们报告了基于人和小鼠GIP序列的GIPR肽拮抗剂与基于脂肪酸的延长的结构-活性关系。我们评估了这些化合物在体外，在DIO小鼠体内，和离体胰岛从人类供体。我们报道了一种GIP（5-31）棕榈酰化类似物[Nα-Ac，L14，R18，E21] hGIP（5-31）-K11（γE-C16）的发现，该类似物在hGIPR和mGIPR上都能有效地抑制体外GIP介导的cAMP生成。在体内，这种肽有效地阻断了响应于外源性和内源性GIP的GIP介导的β-内酰胺酶减少，并显示出适合啮齿动物每日一次给药的循环药代动力学特征。与Semaglutide单药相比，GLP-1 R激动剂Semaglutide和该GIPR肽拮抗剂联合给药可增强体重减轻。最后，这种拮抗剂抑制完整人胰岛中GIP-而不是GLP-1-刺激的胰岛素分泌。我们的工作证明了一种强效、特异性和长效的GIPR肽拮抗剂的发现，该肽拮抗剂在体外、离体人胰岛和小鼠体内有效阻断GIP作用，同时在DIO小鼠中与GLP-1 R激动剂联合使用时产生额外的体重减轻。[Nα-Ac，L14，R18，E21] hGIP（5-31）- K11（γE-C16）是一种有效的特异性GIPR肽拮抗剂。延长化学和位置影响药理学，而不仅仅是PK特征。先导肽显示适合啮齿动物每日一次给药的PK特征。先导拮抗剂可增强GLP-1 R激动剂介导的啮齿类动物体重减轻。在完整的人胰岛中，GIP而不是GLP-1的作用被先导拮抗剂减弱。
Glucose-dependent insulinotropic polypeptide (GIP) is one of the two major incretin factors that regulate metabolic homeostasis. Genetic ablation of its receptor (GIPR) in mice confers protection against diet-induced obesity (DIO), while GIPR neutralizing antibodies produce additive weight reduction when combined with GLP-1R agonists in preclinical models and clinical trials. Conversely, GIPR agonists have been shown to promote weight loss in rodents, while dual GLP-1R/GIPR agonists have proven superior to GLP-1R monoagonists for weight reduction in clinical trials. We sought to develop a long-acting, specific GIPR peptide antagonist as a tool compound suitable for investigating GIPR pharmacology in both rodent and human systems. We report a structure–activity relationship of GIPR peptide antagonists based on the human and mouse GIP sequences with fatty acid-based protraction. We assessed these compounds in vitro, in vivo in DIO mice, and ex vivo in islets from human donors. We report the discovery of a GIP(5-31) palmitoylated analogue, [Nα-Ac, L14, R18, E21] hGIP(5-31)-K11 (γE-C16), which potently inhibits in vitro GIP-mediated cAMP generation at both the hGIPR and mGIPR. In vivo, this peptide effectively blocks GIP-mediated reductions in glycemia in response to exogenous and endogenous GIP and displays a circulating pharmacokinetic profile amenable for once-daily dosing in rodents. Co-administration with the GLP-1R agonist semaglutide and this GIPR peptide antagonist potentiates weight loss compared to semaglutide alone. Finally, this antagonist inhibits GIP- but not GLP-1-stimulated insulin secretion in intact human islets. Our work demonstrates the discovery of a potent, specific, and long-acting GIPR peptide antagonist that effectively blocks GIP action in vitro, ex vivo in human islets, and in vivo in mice while producing additive weight-loss when combined with a GLP-1R agonist in DIO mice. [Nα-Ac, L14, R18, E21] hGIP(5-31) - K11 (γE-C16) is a potent and specific GIPR peptide antagonist. Protraction chemistry and location influences pharmacology, not simply PK profile. The lead peptide displays a PK profile amenable for once-daily dosing in rodents. The lead antagonist potentiates GLP-1R agonist mediated weight loss in rodents. GIP, not GLP-1, action is diminished by the lead antagonist in intact human islets.
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DOI：
10.1152/ajpendo.00577.2005
发表时间：
2006-09-01
影响因子：
5.1
作者：
Deacon, Carolyn F.;Plamboeck, Astrid;Holst, Jens J.
通讯作者：
Holst, Jens J.
影响因子：
5.8
作者：
Irwin, N.;McClean, P. L.;Flatt, P. R.
通讯作者：
Flatt, P. R.
影响因子：
7.7
作者：
Asmar, Meena;Asmar, Ali;Bulow, Jens
通讯作者：
Bulow, Jens
影响因子：
4.1
作者：
Gasbjerg, Laerke S.;Hartmann, Bolette;Knop, Filip K.
通讯作者：
Knop, Filip K.
影响因子：
16.6
作者：
Killion EA;Chen M;Falsey JR;Sivits G;Hager T;Atangan L;Helmering J;Lee J;Li H;Wu B;Cheng Y;Véniant MM;Lloyd DJ
通讯作者：
Lloyd DJ