From the Guidelines
GLP-1 receptor agonists are manufactured through recombinant DNA technology, where bacteria or yeast cells are genetically engineered to produce proteins that mimic human glucagon-like peptide-1 (GLP-1). The process involves inserting the gene for the desired GLP-1 analog into host cells, which then produce the protein in large quantities 1. These proteins are then harvested, purified, and formulated into injectable medications. Some common GLP-1 agonists include semaglutide, liraglutide, dulaglutide, and exenatide, which are delivered by subcutaneous injection and stimulate insulin secretion and reduce glucagon secretion in a glucose-dependent manner 1. The manufacturing process often involves modifications to the natural GLP-1 molecule to extend its half-life in the body, as natural GLP-1 is rapidly degraded by enzymes. For example, structural differences among GLP-1 receptor agonists, such as dulaglutide, exenatide extended-release, and semaglutide, affect duration of action, and their formulation and dosing may affect efficacy for glucose-lowering and weight reduction as well as side effect profile and cardiovascular effects 1. Key characteristics of GLP-1 receptor agonists include:
- High glucose-lowering efficacy with minimal risk for hypoglycemia
- Variation in duration of action and formulation, affecting efficacy and side effects
- Administration via subcutaneous injection, with varying frequencies (e.g., once weekly for semaglutide, dulaglutide, and exenatide extended-release, and once daily for liraglutide and lixisenatide) 1.
From the FDA Drug Label
The peptide backbone is produced by yeast fermentation. The peptide precursor of liraglutide, produced by a process that includes expression of recombinant DNA in Saccharomyces cerevisiae,
GLP-1 receptor agonists are made through a process involving:
- Yeast fermentation to produce the peptide backbone, as seen in semaglutide 2
- Recombinant DNA expression in Saccharomyces cerevisiae to produce the peptide precursor, as seen in liraglutide 3 These processes are used to create the foundation for the GLP-1 receptor agonist molecules.
From the Research
Manufacturing of GLP-1 Receptor Agonists
- GLP-1 receptor agonists are produced using various methods, including recombinant DNA technology 4, 5.
- The manufacturing process for semaglutide, a GLP-1 receptor agonist, involves multistep synthesis and can be challenging due to its large peptide size and hydrophobic fatty acid side chain 6.
- Researchers have developed alternative analogues, such as a glycosylated GLP-1 analogue, which can be produced in higher yields and has similar biological activity to semaglutide 6.
- GLP-1 receptor agonists can be formulated for subcutaneous injection, with some products available in prefilled pens 4.
Characteristics of GLP-1 Receptor Agonists
- GLP-1 receptor agonists have a similar structure to human glucagon-like peptide-1 (GLP-1), but with modifications to increase their stability and half-life 4, 5.
- These modifications can include the addition of a hydrophobic fatty acid side chain or a hydrophilic oligosaccharide 6.
- GLP-1 receptor agonists can be classified as short-acting or long-acting, depending on their duration of action 7.
Research and Development
- Researchers are actively exploring new GLP-1 receptor agonists with improved properties, such as increased potency and duration of action 8.
- The development of small molecule GLP-1 receptor agonists is also an area of research, with potential advantages including lower cost and oral administration 8.
- GLP-1 receptor agonists have shown promise in the treatment of type 2 diabetes and other diseases, and ongoing research aims to further optimize their design and therapeutic applications 7, 8.