| A novel GLP-1 analog, BPI3006, with potent DPP IV resistance and good glucoregulatory effect. | |
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MedLine Citation:
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PMID: 20804731 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Glucagon-like peptide-1 (GLP-1) is an incretin hormone that decreases postprandial glycemic excursions by enhancing insulin secretion but with short half-life due to rapid inactivation by enzymatic N-terminal truncation. Therefore, efforts are being made to improve the stability of GLP-1 via modifying its structure or inhibiting dipeptidyl-peptidase IV (DPP IV), which is responsible for its degradation. Here we report a novel GLP-1 analog BPI3006 with -NHCO- of Ala(8) replaced by -CH(CF(3))NH- and features of its metabolic stability, GLP-1 receptor trans-activation and in vivo biological activity. BPI3006 is highly resistant to DPP IV-mediated degradation with 91.1% of parental peptide left after 24h exposure to the enzyme. BPI3006 also effectively activates its target gene promoter through GLP-1 receptor activation by measuring the transiently transfected reporter gene green fluorescence protein (GFP) expression in NIT-1 cells. Furthermore, BPI3006 could well restrain the glycemia variation in fasted normal ICR mice after a single administration followed by an oral glucose loading. In spontaneous type 2 diabetic KKA(y) mice, BPI3006 injected twice daily could significantly improve the oral glucose tolerance and hyperinsulinemia, as well as ameliorate the food and water consumption. In conclusion, BPI3006 has enhanced resistance to DPP IV leading to improved stability, and shows excellent in vivo biological activity. Thus it may be a new candidate for T2DM treatment and its novel modification may provide valuable guidance for the future development of long-acting GLP-1 analogs. |
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Authors:
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Caina Li; Yi Huan; Ning Shen; Lixia Ji; Sujuan Sun; Shuainan Liu; Quan Liu; Lihui Gao; Fenlai Tan; Yanping Wang; Zhufang Shen |
Publication Detail:
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Type: Journal Article; Research Support, Non-U.S. Gov't Date: 2010-09-06 |
Journal Detail:
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Title: Biochemical and biophysical research communications Volume: 400 ISSN: 1090-2104 ISO Abbreviation: Biochem. Biophys. Res. Commun. Publication Date: 2010 Oct |
Date Detail:
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Created Date: 2010-10-04 Completed Date: 2010-11-23 Revised Date: - |
Medline Journal Info:
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Nlm Unique ID: 0372516 Medline TA: Biochem Biophys Res Commun Country: United States |
Other Details:
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Languages: eng Pagination: 563-8 Citation Subset: IM |
Copyright Information:
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Copyright © 2010 Elsevier Inc. All rights reserved. |
Affiliation:
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Institute of Materia Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, No. 1 Xiannongtan Street, Beijing 100050, China. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Amino Acid Sequence Animals Diabetes Mellitus, Experimental / drug therapy Diabetes Mellitus, Type 2 / drug therapy Dipeptidyl Peptidase 4 / metabolism* Glucagon-Like Peptide 1 / analogs & derivatives*, metabolism*, pharmacology Hypoglycemic Agents / chemistry, metabolism*, pharmacology Male Mice Mice, Inbred ICR Molecular Sequence Data Peptides / chemistry, metabolism*, pharmacology Receptors, Glucagon / agonists* |
| Chemical | |
Reg. No./Substance:
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0/BPI 3006; 0/Hypoglycemic Agents; 0/Peptides; 0/Receptors, Glucagon; 0/glucagon-like peptide receptor; 89750-14-1/Glucagon-Like Peptide 1; EC 3.4.14.5/Dipeptidyl Peptidase 4 |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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