Design and Biosynthesis of Ornithine 8-Containing Semaglutide Variants with a Click Chemistry-Modifiable Position 26.
Study Goal
The researchers aimed to develop a method for generating semaglutide variants, including the incorporation of ornithine at position 8, to improve stability and functionality.
Results Summary
The study introduced a novel approach combining RiPP technology and amber stop codon incorporation to create semaglutide variants, including ornithine at position 8, enhancing resistance to enzymatic cleavage and enabling functional group additions. This method allows for high-throughput screening of optimized peptide-based GLP-1 receptor agonists.
Population
Not specified (in vitro or microbial system implied).
Effective Dosage
Not specified
Duration
Not specified
Interactions
None mentioned
| Intervention | Direction | Endpoint | Population | Dosage | Impact | Claim # |
|---|---|---|---|---|---|---|
Semaglutide | decrease | type 2 diabetes and obesity | - | - | constitutes an effective and widely used treatment | #1 |
Semaglutide | no change | oral bioavailability, gastrointestinal side effects, and costs | - | - | challenges such as insufficient oral bioavailability, gastrointestinal side effects, and high costs persist | #2 |
Optimizing the peptide structure | decrease | insufficient oral bioavailability, gastrointestinal side effects, and high costs | - | - | is crucial for addressing these issues | #3 |
Establishing a rapid method to generate a large library of semaglutide mutants | increase | activity screening | - | - | will enable high-throughput activity screening | #4 |
novel "Fits-In-All" approach that combines ribosomally synthesized and post-translationally modified peptide (RiPP) technology with amber stop codon incorporation | increase | semaglutide variants | - | - | to generate semaglutide variants | #5 |
strategically incorporates noncanonical amino acid ornithine at position 8 utilizing microbial modification enzyme OspR in vivo | decrease | dipeptidyl peptidase-4-mediated cleavage | - | - | To counter dipeptidyl peptidase-4-mediated cleavage | #6 |
functional groups are introduced by an orthogonal tRNA/aminoacyl-tRNA synthetase pair recognizing the amber stop codon at position 26 | increase | linkage of diverse groups | - | - | enabled the click chemistry-based linkage of diverse groups | #7 |
This approach | increase | semaglutide analogues | - | - | allows for the generation of a broad array of semaglutide analogues that can be screened for optimal properties | #8 |
this innovative approach | increase | design and synthesis of optimized peptide-based GLP-1 receptor agonists | - | - | opens new avenues for the design and synthesis of optimized peptide-based GLP-1 receptor agonists | #9 |
Semaglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, constitutes an effective and widely used treatment for type 2 diabetes and obesity. However, challenges such as insufficient oral bioavailability, gastrointestinal side effects, and high costs persist. Overcoming these limitations is essential for improving patient compliance and semaglutide's safety profile. While advanced technologies such as oral delivery systems offer partial solutions, optimizing the peptide structure is crucial for addressing these issues. Establishing a rapid method to generate a large library of semaglutide mutants will enable high-throughput activity screening. In this study, we introduce a novel "Fits-In-All" approach that combines ribosomally synthesized and post-translationally modified peptide (RiPP) technology with amber stop codon incorporation to generate semaglutide variants. To counter dipeptidyl peptidase-4-mediated cleavage, our method strategically incorporates noncanonical amino acid ornithine at position 8 utilizing microbial modification enzyme OspR in vivo. Furthermore, functional groups are introduced by an orthogonal tRNA/aminoacyl-tRNA synthetase pair recognizing the amber stop codon at position 26, which enabled the click chemistry-based linkage of diverse groups. This approach allows for the generation of a broad array of semaglutide analogues that can be screened for optimal properties. In conclusion, this innovative approach opens new avenues for the design and synthesis of optimized peptide-based GLP-1 receptor agonists.