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Multiparameter Peptide Optimization toward Stable Triple Agonists for the Treatment of Diabetes and Obesity
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.
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Unimolecular triple agonists with time-action appropriate for once-daily clinical administration demonstrate the metabolic benefits of the three combined activities in preclinical settings.
“In support of this notion, unimolecular triple agonists with time-action appropriate for once-daily clinical administration demonstrate the metabolic benefits of the three combined activities in preclinical settings [43,46]”
From Next generation GLP-1/GIP/glucagon triple agonists normalize body weight in obese mice (2022) · cites this paper as [46]
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“In support of this notion, unimolecular triple agonists with time-action appropriate for once-daily clinical administration demonstrate the metabolic benefits of the three combined activities in preclinical settings [43,46].”
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Peptide Marriages: Modular Assembly of Multi‐Agonist Therapeutics
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Metadata
- Authors
- Evers, A., Pfeiffer‐Marek, S., Bossart, M., Elvert, R., Lorenz, K., Heubel, C., Garea, A. V., Schroeter, K., Riedel, J., Stock, U., Konkar, A., & Wagner, M.
- Affiliations
- Sanofi (Germany) (DE)
- R&D, Sanofi‐Aventis Deutschland GmbH, Industriepark Höchst Frankfurt am Main D‐65926 Germany
- Corresponding author
- Evers, Andreas
- Wagner, Michael
- Venue
- Advanced Therapeutics
- Publisher
- Wiley
- Published
- 2020-06-11
- Volume
- 3
- Issue
- 9
- ISSN
- 2366-3987 (ISSN-L)
- OpenAlex
- W3034475447
- Semantic Scholar
- a406db48c3fa6f411858bf5318932f38fa4d939c
- Cited by
- 9
- References
- 21
- Citations by year
- 2026: 1 · 2025: 2 · 2023: 1 · 2022: 3 · 2021: 2
- FWCI
- 1.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Advanced Therapeutics (publishedVersion)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Physical Sciences › Chemistry › Organic Chemistry › Chemical Synthesis and Analysis
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuropeptides and Animal Physiology
- Keywords
- peptide optimization, GLP-1 receptor, glucagon receptor, GIP receptor, diabetes treatment, obesity treatment, physicochemical stability, subcutaneous administration, pharmacokinetics, pharmacodynamics, minipigs, monkeys
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