Novel Exenatide Analogs with Peptidic Albumin Binding Domains: Potent Anti-Diabetic Agents with Extended Duration of Action

Autor: David G. Parkes, Diane R. Yuskin, Christopher J. Soares, Shijun Steven Ren, Lawrence J. D'souza, Odile Esther Levy, Carolyn M. Jodka, Krystyna Tatarkiewicz, Soumitra S. Ghosh, Abhinandini Sharma, Manoj P. Samant, Lala Mamedova, Li Jenny Jin
Rok vydání: 2014
Předmět:
Male
Proteomics
Anatomy and Physiology
lcsh:Medicine
Administration
Oral
Peptide
Pharmacology
Biochemistry
Mice
chemistry.chemical_compound
Endocrinology
Drug Stability
Oral administration
Drug Discovery
Receptors
Glucagon
Peptide synthesis
lcsh:Science
chemistry.chemical_classification
Glucose tolerance test
Multidisciplinary
medicine.diagnostic_test
biology
Chemistry
Clinical Pharmacology
Medicine
Protein Binding
Research Article
Biotechnology
medicine.drug
Drugs and Devices
medicine.medical_specialty
Drug Research and Development
Serum albumin
Endocrine System
Glucagon-Like Peptide-1 Receptor
Diabetes Mellitus
Experimental
Pharmacokinetics
Albumins
Internal medicine
medicine
Animals
Humans
Hypoglycemic Agents
Synthetic Peptide
Protein Interaction Domains and Motifs
Biology
Diabetic Endocrinology
Binding Sites
Endocrine Physiology
Venoms
lcsh:R
Albumin
Glucose Tolerance Test
Diabetes Mellitus Type 2
Hormones
Rats
Disease Models
Animal
Kinetics
Macaca fascicularis
Pharmacodynamics
biology.protein
Exenatide
lcsh:Q
Medicinal Chemistry
Peptides
Zdroj: PLoS ONE
PLoS ONE, Vol 9, Iss 2, p e87704 (2014)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0087704
Popis: The design, synthesis and pharmacology of novel long-acting exenatide analogs for the treatment of metabolic diseases are described. These molecules display enhanced pharmacokinetic profile and potent glucoregulatory and weight lowering actions compared to native exenatide. [Leu(14)]exenatide-ABD is an 88 residue peptide amide incorporating an Albumin Binding Domain (ABD) scaffold. [Leu(14)]exenatide-ABP is a 53 residue peptide incorporating a short Albumin Binding Peptide (ABP). [Leu(14)]exenatide-ABD and [Leu(14)]exenatide-ABP exhibited nanomolar functional GLP-1 receptor potency and were metabolically stable in vitro in human plasma and in a pancreatic digestive enzyme mixture. Both molecules displayed picomolar and nanomolar binding association with albumin across multiple species and circulating half lives of 16 and 11 hours, respectively, post a single IV dose in rats. Unlike exenatide, both molecules elicited robust glucose lowering when injected 1 day prior to an oral glucose tolerance test, indicative of their extended duration of action. [Leu(14)]exenatide-ABD was compared to exenatide in a Lep (ob/ob) mouse model of diabetes. Twice-weekly subcutaneously dosed [Leu(14)]exenatide-ABD displayed superior glucose lowering and weight loss in diabetic mice when compared to continuously infused exenatide at the same total weekly dose. A single oral administration of each molecule via an enteric coated capsule to cynomolgus monkeys showed superior pharmacokinetics for [Leu(14)]exenatide-ABD as compared to [Leu(14)]exenatide-ABP with detectable exposure longer than 14 days. These studies support the potential use of these novel long acting exenatide analogs with different routes of administration for the treatment of type 2 diabetes.
Databáze: OpenAIRE
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