GLP-1R Agonistic Peptides with Reduced Receptor Activity
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Solution Overview
Problem
GLP-1R agonistic peptides used alone or in combination with other active pharmaceutical ingredients, such as FGF21 compounds, often result in adverse effects like nausea and vomiting due to their pharmacological activity levels, necessitating the development of peptides with reduced GLP-1R agonistic activity to balance therapeutic effects while minimizing adverse reactions.
Innovation Solution
Development of GLP-1R agonistic peptides with significantly reduced GLP-1R agonistic activity, specifically designed to have activity levels between 9- to 531-fold lower than native GLP-1(7-36), comprising specific amino acid sequences that can be part of fusion molecules or used alone, to achieve balanced therapeutic effects without adverse effects.
Engineering Contradictions & Design Principles
Engineering Contradiction Analysis
1Reliability
If GLP-1R agonistic peptides are administered at higher plasma levels to achieve pharmacological effects, then therapeutic efficacy is improved, but adverse effects such as nausea and vomiting increase
Solution Approach 1:
The patent modifies the amino acid sequence of GLP-1R agonistic peptides by substituting specific residues (e.g., positions 8, 13, 18, 26, 27, 28, 30, 31, 32, 33, 34, 35) to reduce GLP-1R agonistic activity by 9- to 531-fold. This parameter change in molecular structure allows the peptide to maintain metabolic effects while reducing gastrointestinal adverse effects at therapeutic plasma levels
Solution Approach 2:
The invention introduces specific amino acid substitutions at critical positions within the GLP-1 peptide sequence to create localized changes in receptor binding affinity. These targeted modifications at specific residues alter the interaction with GLP-1R in a way that differentially affects pharmacological effects versus adverse effects, achieving selective modulation of activity
2Reliability
If GLP-1R agonistic peptides are used alone, then GLP-1-mediated pharmacological effects are achieved, but the risk of adverse effects increases
Solution Approach 1:
The patent creates modified GLP-1R agonistic peptides with altered amino acid sequences that fundamentally change the activity profile. These parameter changes enable the peptide to achieve metabolic therapeutic effects through alternative mechanisms or receptor interactions that bypass the pathways leading to gastrointestinal adverse effects
3Reliability
If fusion molecules combining GLP-1R agonistic peptides and FGF21 compounds are administered, then combined therapeutic benefits are achieved, but GLP-1-mediated adverse effects may still occur
Solution Approach 1:
The patent modifies the GLP-1R agonistic peptide component within fusion molecules by implementing specific amino acid substitutions. These parameter changes reduce the GLP-1R agonistic activity of the peptide portion, thereby maintaining the combined therapeutic benefits of the fusion molecule while minimizing GLP-1-mediated gastrointestinal adverse effects
Data Source
AI summary
The present invention relates to Glucagon-Like Peptide-1 Receptor (GLP-1R) agonistic peptides with reduced GLP-1R CA agonistic activity, and fusion molecules comprising the same. The present invention also relates to nucleic acid molecules encoding GLP-1R agonistic peptides with reduced GLP-1R agonistic activity, pharmaceutical compositions and combinations comprising GLP-1R agonistic peptides with reduced GLP-1R agonistic activity, and kits including GLP-1R agonistic peptides with reduced GLP-1R agonistic activity. The present invention further relates to the use of GLP-1R agonistic peptides with reduced GLP-1R agonistic activity as medicaments, in particular, for the treatment of obesity, being overweight, metabolic syndrome, diabetes mellitus, diabetic retinopa-CA thy, hyperglycemia, dyslipidemia, NASH and/or atherosclerosis.