Multiparameter Peptide Optimization toward Stable Triple Agonists for the Treatment of Diabetes and Obesity. Issue 9 (11th June 2020)

• Record Type: Journal Article
• Authors: Evers, Andreas; Pfeiffer‐Marek, Stefania; Bossart, Martin; Elvert, Ralf; Lorenz, Katrin; Heubel, Christoph; Garea, Ana Villar; Schroeter, Katrin; Riedel, Jens; Stock, Ursula; Konkar, Anish; Wagner, Michael
• Is Part Of: Advanced therapeutics. Volume 3:Issue 9(2020)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2020-06-11
• Subjects: drug delivery -- drug discovery -- medicinal chemistry -- molecular modeling -- peptide therapeutics; Therapeutics -- Periodicals; Pharmaceutical technology -- Periodicals; Pharmacogenetics -- Periodicals; 615.5
• DOI: 10.1002/adtp.202000052
• Languages: English
• ISSNs: 2366-3987

Abstract

Abstract: Historically, peptide optimization has mainly focused on pharmacological activity. Physicochemical properties have often been evaluated late in discovery, potentially providing molecules with suboptimal stability properties. Often, such issues cannot be overcome by formulation approaches but need additional optimization cycles for a redesign of the peptide. Here, early rational multiparameter optimization of exendin‐4 based agonists is described toward i) a balanced triple activity profile at the glucagon‐like peptide 1, glucagon, and gastric inhibitory polypeptide receptors for the treatment of diabetes and obesity and in parallel ii) robust physicochemical properties for 1‐daily subcutaneous application in a multiple‐dose pen device. In depth evaluation of an optimized candidate shows an excellent profile with respect to its physicochemical properties and pharmacokinetic/pharmacodynamic (PD) behavior in minipigs and monkeys. Abstract : Multiparameter optimization of peptides: In addition to a peptides activity, its solubility, long‐term physical and chemical stability, and compatibility with formulation requirements are crucial parameters that determine the developability of a peptide into a commercial drug product. Here, iterative peptide optimization toward stable agonists with multiple receptor activities for the treatment of obesity and diabetes is described.