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.
Department of Materials Science and Engineering, Pohang University of Science and Technology (POSTECH), Pohang, Kyungbuk, Republic of Korea.
Ji-Hyun
JH
Kong
Eun Ju
EJ
Oh
Su Young
SY
Chae
Kang Choon
KC
Lee
Sei Kwang
SK
Hahn
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