Development of bioactive stable secretin agonists

Project: Research project

Project Details

Description

Development of bioactive stable secretin agonists Development of bioactive, stable, secretin agonists for the potential treatment of obesity and diabetes: first-in-class therapeutics for critical clinical problems Obesity is a major public health problem, increasing in incidence and severity around the world, and a priority focus of the ASU-Mayo Collaboration. This is directly responsible for the increasing incidence of diabetes and its complications and co-morbidities. Modification of diet and lifestyle reduce weight in the short-term, but is typically not durable, and bariatric surgery has been very effective for morbid obesity, but is not scalable for this cohort. Lessons from bariatric surgery, however, have focused attention on gut peptides and possible leads to new therapeutics. GLP-1 agonists are the most recent example of a promising new drug, but it is not yet clear that these will be safe and effective, particularly for non-diabetic patients. The surgical approach most effective for weight loss and reversal of diabetes is Roux-En-Y gastric bypass (RYGB), pointing to the duodenum as the source of a factor that can yield metabolic benefits even before weight loss occurs. We postulate that secretin may be this previously unidentified factor, based on its influence on vagal afferents to induce satiety, on pancreatic islets to stimulate insulin secretion in a glucose-dependent manner, and on adipocytes where it is thermogenic. It also has potential beneficial effects on heart and vasculature that could also be useful to treat another morbidity of this spectrum of diseases. In the setting of RYGB, gastric acid, the major stimulant of secretin secretion by duodenal S cells, remains unbuffered and can produce high levels of this peptide. Natural secretin, while known to be safe as administered parenterally for acute diagnostic purposes, has a very short biological half-life that interferes with its usefulness as a therapeutic agent, and no other secretin agonists have yet been described. Peptides have returned to favor as approved therapeutics, with modern peptide chemistry techniques, such a stapling, introduction of non-canonical amino acids, and backbone cyclization shown to be very effective in improving the ADME (absorption, distribution, metabolism, elimination) properties. This project will for the first time bring together Dr. Miller with secretin/secretin receptor expertise and Dr. Ghirlanda with peptide chemistry expertise, to take advantage of these approaches to prepare and characterize secretin receptor agonists with potential for treating this spectrum of diseases. This will include two approaches: (i) full length natural secretin(1-27) analogues with residue changes and protein conjugation that have been proven to be useful for other family members to minimize proteolysis and/or clearance, and (ii) shortened secretin analogues representing minimal length compatible with high affinity binding and full biological activity, working toward possible orally-active agents. Peptide analogues would be jointly designed, synthesized and chemically characterized at ASU, and biologically characterized (binding affinity, agonist potency, specificity) at Mayo, with this cycle repeated based on characteristics of each iteration of compounds. These in vitro data will be key for supporting a shared NIH grant application within 18 months that would include in vivo pre-clinical testing of the most promising agents, as well as moving toward proof-of-principle clinical studies. This would ultimately be followed by formal efforts to develop a first-in-class therapeutic drug.
StatusFinished
Effective start/end date12/5/176/30/19

Funding

  • Mayo Clinic: Center for Regenerative Medicine: $25,000.00

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