title: Site-specific fatty chain-modified exenatide analogs with balanced glucoregulatory activity and prolonged in vivo activity.
abstract: The therapeutic utility of exenatide (Ex-4) is limited due to short plasma half-life of 2.4h and thus numerous approaches have been used to obtain a longer action time. However, such strategies often attend to one thing and lose another. The study aimed to identify a candidate with balanced glucoregulatory activity and prolonged in vivo activity. A series of fatty chain conjugates of Ex-4 were designed and synthesized. First, thirteen cysteine modified peptides (1-13) were prepared. Peptides 1, 10, and 13 showed improved glucagon-like peptide-1 (GLP-1) receptor activate potency and were thus selected for second step modifications to yield conjugates I-1-I-9. All conjugates retained significant GLP-1 receptor activate potency and more importantly exerted enhanced albumin-binding properties and in vitro plasma stability. The protracted antidiabetic effects of the most stable I-3 were further confirmed by both multiple intraperitoneal glucose tolerance test and hypoglycemic efficacies test in vivo. Furthermore, once daily injection of I-3 to streptozotocin (STZ) induced diabetic mice achieved long-term beneficial effects on hemoglobin A1C (HbA1C) lowering and glucose tolerance. Once daily injection of I-3 to diet induced obesity (DIO) mice also achieved favorable effects on food intake, body weight, and blood chemistry. Our results suggested that I-3 was a promising agent deserving further investigation to treat obesity patients with diabetes.
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Lidan
authors.initials: L
authors.lastname: Sun
authors.affiliation: Division of Antitumor Pharmacology, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 200090, China.
authors.forename: Xun
authors.initials: X
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China; School of Chemistry and Chemical Engineering, Jiangsu Normal University, Xuzhou 221116, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Han
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Xingguang
authors.initials: X
authors.lastname: Cai
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yuxuan
authors.initials: Y
authors.lastname: Dai
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China.
authors.forename: Yingying
authors.initials: Y
authors.lastname: Chu
authors.affiliation: Key Laboratory of Stem Cell Biology, Institute of Health Sciences, Shanghai Jiao Tong University School of Medicine and Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Chuandong
authors.initials: C
authors.lastname: Wang
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: ydhuangwenlong@126.com.
authors.forename: Wenlong
authors.initials: W
authors.lastname: Huang
authors.affiliation: Jiangsu Key Laboratory of Drug Discovery for Metabolic Diseases and State Key Laboratory of Natural Medicines, Center of Drug Discovery, China Pharmaceutical University, 24 Tongjiaxiang, Nanjing 210009, China. Electronic address: qianhai24@163.com.
authors.forename: Hai
authors.initials: H
authors.lastname: Qian
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D059305:Diet, High-Fat / Q000009:adverse effects; D015195:Drug Design; D000077270:Exenatide; D005227:Fatty Acids / Q000737:chemistry*; D005449:Fluorenes / Q000737:chemistry; D005786:Gene Expression Regulation; D000067757:Glucagon-Like Peptide-1 Receptor / Q000235:genetics / Q000378:metabolism; D005951:Glucose Tolerance Test; D006442:Glycated Hemoglobin / Q000037:antagonists & inhibitors / Q000096:biosynthesis; D057809:HEK293 Cells; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013311:Streptozocin; D014688:Venoms / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000494:pharmacology*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000077270:Exenatide; D005227:Fatty Acids; D005449:Fluorenes; D000067757:Glucagon-Like Peptide-1 Receptor; D006442:Glycated Hemoglobin; D007004:Hypoglycemic Agents; D010455:Peptides; D013311:Streptozocin; D014688:Venoms; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: Cysteine modified; Ex-4; Fatty chain; Protracted antidiabetic effects