Stable GLP-1 Agonists
Incretin hormones, such as glucagon-like peptide (GLP)-1, represent a promising area of research in the fight against diabetes because these hormones stimulate glucose-dependent insulin secretion from the pancreas and assist in glucose homeostasis. Additionally, GLP-1 slows the rate at which nutrients are absorbed into the bloodstream, thereby reducing food intake and inducing weight loss. GLP-1 may also play a role in beta-cell neogenesis, which could have a profound impact on progressive beta-cell decline. Such positive glucoregulatory actions of GLP-1 make it a promising replacement therapy for diabetes.1
Unfortunately, native GLP-1 has an extremely short half-life because it is degraded by a proteolytic enzyme, dipeptidylpeptidase (DPP) IV. DPP IV is a ubiquitously expressed serine protease that exhibits postproline or alanine peptidase activity. Because GLP-1 has an alanine residue at position 2, GLP-1 is a substrate for DPP IV and is rapidly degraded in the gut.1
To blunt the negative effects of DPP IV, significant research is being conducted to develop inhibitors of DPP IV and to develop stable forms of GLP-1, which are more resistant to enzymatic degradation, thereby increasing the circulating half-life.1 Arisaph has designed and synthesized several stable GLP-1 analogs that have been shown to be resistant to DPP IV degradation and have been shown to have long-lasting effects on glucose lowering in preclinical animal studies. Such stable analogs are human derived and thus are not expected to induce antibody formation. Arisaph is currently exploring alternative routes (e.g., nasal) of delivery for its stable GLP-1 analogs in order to improve patient compliance. Additionally, Arisaph is applying various chemistry approaches to develop orally active GLP-1 agonists that are projected to maintain the efficacy of stable GLP-1 analogs without being degraded in the GI tract.
- Chemical & Engineering News website. Available at: http://pubs.acs.org/cen/coverstory/8243/8243diabetes.html. Accessed April 24, 2008