首页|Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis

Design and discovery of a highly potent ultralong-acting GLP-1 and glucagon co-agonist for attenuating renal fibrosis

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The role of co-agonists of glucagon-like peptide-1 receptor(GLP-1 R)and glucagon receptor(GCGR)in chronic kidney disease(CKD)remains unclear.Herein we found that GLP-1 R and GCGR expression levels were lower in the kidneys of mice with CKD compared to healthy mice and were correlated with disease severity.Interestingly,GLP-1 R or GCGR knockdown aggravated the progression of kidney injury in both diabetic db/db mice and non-diabetic mice undergoing unilateral ureteral obstruc-tion(UUO).Based on the importance of GLP-1R and GCGR in CKD,we reported a novel monomeric peptide,1907-B,with dual-agonism on both GLP-1R and GCGR.The data confirmed that 1907-B had a longer half-life than long-acting semaglutide in rats or cynomolgus monkeys(～2-3 fold)and exhibited better therapeutic contribution to CKD than best-in-class monoagonists,semaglutide,or glucagon,in db/db mice and UUO mice.Various lock-of-function models,including selective pharmacological activation and genetic knockdown,confirmed that 1907-B's effects on ameliorating diabetic nephropathy in db/db mice,as well as inhibiting kidney fibrosis in UUO mice,were mediated through GLP-1 and glucagon signaling.These findings highlight that 1907-B,a novel GLP-1R and GCGR co-agonist,exerts multifactorial improvement in kidney injuries and is an effective and promising therapeutic option for CKD treatment.

GLP-1 receptorGlucagon receptorChronic kidney diseaseDiabetic nephropathyKidney fibrosisDual-agonism

Qian Zhao、Jiale Dong、Han Liu、Hui Chen、Huan Yu、Shuyin Ye、Shuangjin Yu、Yu Li、Longhui Qiu、Nazi Song、Hongjiao Xu、Qi Liu、Zhiteng Luo、Yuyi Li、Rui Wang、Guodong Chen、Xianxing Jiang

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School of Pharmaceutical Sciences,Guangdong Provincial Key Laboratory of Chiral Molecule and Drug Discovery,Sun Yat-sen University,Guangzhou 510006,China

Shenzhen Turier Biotech.Co.,Ltd.,Shenzhen 518118,China

Organ Transplant Center,the First Affiliated Hospital,Sun Yat-sen University,Guangzhou 510006,China

Zhongshan School of Medicine,Sun Yat-sen University,Guangzhou 510006,China

School of Life Sciences,Key Iaboratory of Preclinical Study for New Drugs of Gansu Province,School of Basic Medical Sciences & Research Unit of Peptide Science,Chinese Academy of Medical Sciences,Lanzhou University,Lanzhou 730000,China

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国家自然科学基金国家自然科学基金Medical Innovation and Development Project of Lanzhou UniversityUndergraduate Teaching Quality Engineering Project of Sun Yatsen UniversityGuangdong Provincial Key Laboratory of Construction Foundation

8227376181871257lzuyxcx-2022-156[2021]932023B1212060022

2024

10.1016/j.apsb.2023.11.020

药学学报(英文版)

药学学报(英文版)

CSTPCD
ISSN：
年,卷(期)：2024.14(3)
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