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PloS one
2014;9 (2): e87704.

Novel exenatide analogs with peptidic albumin binding domains: potent anti-diabetic agents with extended duration of action.

Odile E Levy, Carolyn M Jodka, Shijun Steven Ren, Lala Mamedova, Abhinandini Sharma, Manoj Samant, Lawrence J D'Souza, Christopher J Soares, Diane R Yuskin, Li Jenny Jin, David G Parkes, Krystyna Tatarkiewicz, Soumitra S Ghosh
Author Information
  1. Odile E Levy: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  2. Carolyn M Jodka: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  3. Shijun Steven Ren: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  4. Lala Mamedova: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  5. Abhinandini Sharma: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  6. Manoj Samant: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  7. Lawrence J D'Souza: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  8. Christopher J Soares: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  9. Diane R Yuskin: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  10. Li Jenny Jin: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  11. David G Parkes: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  12. Krystyna Tatarkiewicz: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
  13. Soumitra S Ghosh: Amylin Pharmaceuticals LLC, San Diego, California, United States of America.
PMID: 24503632 DOI: 10.1371/journal.pone.0087704

Abstract

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.

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MeSH Term

Administration, Oral
Albumins
Animals
Binding Sites
Diabetes Mellitus, Experimental
Disease Models, Animal
Drug Stability
Exenatide
Glucagon-Like Peptide-1 Receptor
Glucose Tolerance Test
Humans
Hypoglycemic Agents
Kinetics
Macaca fascicularis
Male
Mice
Peptides
Protein Binding
Protein Interaction Domains and Motifs
Rats
Receptors, Glucagon
Venoms

Chemicals

Albumins
GLP1R protein, human
Glp1r protein, mouse
Glp1r protein, rat
Glucagon-Like Peptide-1 Receptor
Hypoglycemic Agents
Peptides
Receptors, Glucagon
Venoms
Exenatide
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 9

Word Cloud

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