ACS chemical biology: chemical modification to improve the stability of the first exenatide

Exenatide is a type 1 glucagon like peptide (GLP-1) receptor agonist It is an artificial peptide amide composed of 39 amino acids It is a subcutaneous injection Exenatide was approved by FDA in 2006 to treat type 2 diabetes mellitus At present, about 6 million diabetic patients are using the drug A recent study published in the lancet suggests that exenatide may also have the potential to relieve symptoms of Parkinson's disease Asparagine and glutamine (source: C & EN) however, exenatide requires at least one subcutaneous injection per week The FDA has suggested that frequent use of exenatide may increase the risk of pancreatitis and pancreatic cancer Recently, University of California (San Francisco, UCSF) drug chemist DanielV Santi and colleagues adjusted an amino acid of of and linked it to hydrogel microspheres (HydrogCI microspheres, HMs), trying to improve it into a long-acting drug In rodent tests, the new exenatide can be injected once a month To prolong the half-life of the drug The Santi team used the pH dependent junction to connect the peptide to the hydrogel microsphere and try to prepare a new drug that could release slowly within a month But in animal trials, the half-life of the new drug peaked two weeks later When researchers analyzed the structure of the drug, they found that the two amino acid sequences were asparagine, followed by glycine When asparagine lost its amide group and rearranged, they usually degraded By changing asparagine into glutamine, which is not easy to de amide, researchers have stabilized the drug structure By extending the amino acid side chain, the Santi team extended the half-life from about two weeks to six months In animal experiments, the effect of the more stable version in mice was basically the same as that of exenatide In the experiment of modified isessin, which was attached to hydrogel microspheres, the half life of the drug in obese and diabetic rats was one month Since exenatide has been widely studied in clinical practice, Santi hopes to promote the modified drug to clinical trials as soon as possible A more stable exenatide plus hydrogel combination can reduce the cost of medication and reduce the side effects of drugs In theory, the technology could also be used to produce other long-acting drugs, depending on the potency and stability of the original molecules, says Santi Paper link: http://pubs.acs.org/doi/abs/10.1021/accchembio.7b00218