GLP-1 Glucagon Co-agonists Stabilized by Amino Acid Substitutions
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Solution Overview
Problem
Current GLP-1/glucagon receptor co-agonists face challenges with poor physical and chemical stability, which affects their efficacy and duration of action in treating obesity and diabetes.
Innovation Solution
Development of novel GLP-1 derivatives with specific amino acid substitutions, including desaminohistidine at position 7 and histidine at position 9, and the incorporation of negatively charged moieties, which enhance stability, receptor binding, and pharmacokinetic properties, such as prolonged half-life and improved solubility.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1/glucagon receptor co-agonists are developed to achieve robust weight reduction and improved metabolic parameters, then therapeutic efficacy is enhanced, but physical and chemical stability deteriorates
Solution Approach 1:
The patent applies parameter changes by modifying specific amino acid residues at positions 7, 8, and 9 of the GLP-1 derivative structure. These structural parameter changes enable the molecule to achieve both robust therapeutic efficacy through balanced dual receptor activation and improved physical/chemical stability, resolving the contradiction between efficacy and stability
Solution Approach 2:
The patent creates a composite molecular structure that combines features of both GLP-1 and glucagon ligands into a single co-agonist molecule. This composite approach allows the derivative to activate both receptors effectively while incorporating stabilizing modifications, thereby achieving both enhanced efficacy and improved stability simultaneously
2Duration of action of moving object
If GLP-1/glucagon receptor co-agonists are designed for prolonged action, then duration of effect is extended, but molecular complexity increases
Solution Approach 1:
The patent extends duration of action through targeted parameter changes at positions 7, 8, and 9 of the GLP-1 derivative. These specific structural modifications prolong the drug's action without requiring extensive molecular complexity, achieving extended duration through focused optimizations rather than overall molecular expansion
Data Source
Figure 1
AI summary
The application concerns stable and protracted GLP-1 derivatives which are GLP-l/glucagon receptor co-agonists, compositions thereof, use of the GLP-1 derivatives in medicine, and to methods of treatment comprising administration of the GLP-1 derivatives to patients, including treatment of diabetes, obesity and related diseases and conditions. Prefered GLP-1 derivatives comprise a polypeptide consisting of the amino acid sequence of Formula I: lmp-X8-His-Gly-Thr-Phe-Thr-Ser-Asp-Xl 6-Ser-Xi 8-Tyr-Leu-Glu-X22- X23-Ala-Ala -X26-X27-Phe-I le-Ala-Trp-Leu-X33-X34-X35-X36-X37 [I], wherein - X8 is Ala, Aib, Acb, or Gly; - X16 is Val, Leu, lie, or Tyr; - X18 is Lys or Arg; - X22 is Gly, Ala, Glu, Lys, Arg, Ser, orAib; - X23 is Gin, Arg, or Lys; - X26 is Lys or Arg; - X27 is Glu or Lys; - X33 is Val, Leu, or lle; - X34 is Lys or Arg; - X35 is Gly, Thr, Lys, or is absent; - X36 is Ala, Gly, Lys, Ser, or is absent; - X37 is Gly or is absent; wherein said GLP-i derivative further comprises a substituent comprising a lipophilic moiety and at least two negatively charged moieties, wherein one of said negatively charged moieties is distal of a lipophilic moiety; wherein said polypeptide optionally comprises a C-terminal amide; or a pharmaceutically acceptable salt and/or ester thereof.