Long acting hyaluronate--exendin 4 conjugate for the treatment of type 2 diabetes.
Despite clinical exploitation of exendin 4 for the treatment of type 2 diabetes, the significantly short half-life requiring twice a day injection has limited the wide applications. In this work, a protocol for the synthesis of long acting hyaluronate (HA) - exendin 4 conjugate was successfully developed using Michael addition chemistry between vinyl sulfone modified HA (HA-VS) and thiolated exendin 4. The exendin 4 content could be controlled in the range of 5-30 molecules per single HA chain with a bioconjugation efficiency higher than 90%. The conjugation of exendin 4 with HA resulted in about 20 times improved in vitro serum stability maintaining the hypoglycemic and gluco-regulatory bioactivities of exendin 4. HA - exendin 4 conjugates showed excellent glucose-lowering capabilities in type 2 db/db mice demonstrating protracted hypoglycemic effect up to 3 days after a single subcutaneous injection. Furthermore, insulin immunohistochemical analysis of islets in db/db mice confirmed the improved insulinotropic activity of HA - exendin 4 conjugates. The HA - exendin 4 conjugates will be investigated further as a twice a week injection dosage form for clinical applications.
Kong
Ji-Hyun
JH
Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
Oh
Eun Ju
EJ
Chae
Su Young
SY
Lee
Kang Choon
KC
Hahn
Sei Kwang
SK
D000818:Animals; D002850:Chromatography, Gel; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000188:drug therapy*; D000077270:Exenatide; D005947:Glucose / Q000494:pharmacology; D005951:Glucose Tolerance Test; D006801:Humans; D006820:Hyaluronic Acid / Q000097:blood / Q000138:chemical synthesis / Q000737:chemistry / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007274:Injections, Intraperitoneal; D007328:Insulin / Q000378:metabolism; D007515:Islets of Langerhans / Q000187:drug effects / Q000473:pathology; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D051379:Mice; D010455:Peptides / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*; D013450:Sulfones / Q000138:chemical synthesis / Q000737:chemistry; D014688:Venoms / Q000097:blood / Q000737:chemistry / Q000627:therapeutic use*
D007328:Insulin; D010455:Peptides; D013450:Sulfones; D014688:Venoms; C009873:divinyl sulfone; D006820:Hyaluronic Acid; D000077270:Exenatide; D005947:Glucose