title: A novel exendin-4 human serum albumin fusion protein, E2HSA, with an extended half-life and good glucoregulatory effect in healthy rhesus monkeys.
abstract: Glucagon-like peptide-1 (GLP-1) has attracted considerable research interest in terms of the treatment of type 2 diabetes due to their multiple glucoregulatory functions. However, the short half-life, rapid inactivation by dipeptidyl peptidase-IV (DPP-IV) and excretion, limits the therapeutic potential of the native incretin hormone. Therefore, efforts are being made to develop the long-acting incretin mimetics via modifying its structure. Here we report a novel recombinant exendin-4 human serum albumin fusion protein E2HSA with HSA molecule extends their circulatory half-life in vivo while still retaining exendin-4 biological activity and therapeutic properties. In vitro comparisons of E2HSA and exendin-4 showed similar insulinotropic activity on rat pancreatic islets and GLP-1R-dependent biological activity on RIN-m5F cells, although E2HSA was less potent than exendin-4. E2HSA had a terminal elimation half-life of approximate 54 h in healthy rhesus monkeys. Furthermore, E2HSA could reduce postprandial glucose excursion and control fasting glucose level, dose-dependent suppress food intake. Improvement in glucose-dependent insulin secretion and control serum glucose excursions were observed during hyperglycemic clamp test (18 h) and oral glucose tolerance test (42 h) respectively. Thus the improved physiological characterization of E2HSA make it a new potent anti-diabetic drug for type 2 diabetes therapy.
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Ling
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Zhiyun
authors.initials: Z
authors.lastname: Meng
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Gan
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Ruolan
authors.initials: R
authors.lastname: Gu
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Zhuona
authors.initials: Z
authors.lastname: Wu
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gao
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Xiaoxia
authors.initials: X
authors.lastname: Zhu
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Wenzhong
authors.initials: W
authors.lastname: Sun
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Li
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zheng
authors.affiliation: Laboratory of Hematological Pharmacology, State Key Laboratory of Drug Metabolism, Beijing Institute of Transfusion Medicine, China. Electronic address: douguifang@vip.163.com.
authors.forename: Guifang
authors.initials: G
authors.lastname: Dou
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000378:metabolism; D000077270:Exenatide; D052216:Glucagon-Like Peptide 1 / Q000819:agonists; D005947:Glucose / Q000378:metabolism; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism; D008253:Macaca mulatta; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D012709:Serum Albumin / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*; D000075462:Serum Albumin, Human; D014688:Venoms / Q000737:chemistry / Q000493:pharmacokinetics / Q000627:therapeutic use*
chemical_list: C000609727:E2HSA protein; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D011993:Recombinant Fusion Proteins; D012709:Serum Albumin; D014688:Venoms; D052216:Glucagon-Like Peptide 1; D000077270:Exenatide; D005947:Glucose; D000075462:Serum Albumin, Human
keywords: Anti-diabetic drug; Exendin-4; Glucagon-like peptide-1; Pharmacokinetics; Type 2 diabetes