Enzymatic mono-pegylation of glucagon-like peptide 1 towards long lasting treatment of type 2 diabetes

Publication date: 2012 Source:Results in Pharma Sciences, Volume 2 Author(s): Fabio Selis , Rodolfo Schrepfer , Riccardo Sanna , Silvia Scaramuzza , Giancarlo Tonon , Simona Dedoni , Pierluigi Onali , Gaetano Orsini , Stefano Genovese Human glucagon-like peptide-1 (GLP-1) is a physiological gastrointestinal peptide with glucose-dependent insulinotropic effects which is therefore considered an interesting antidiabetic agent. However, after in vivo administration, exogenous GLP-1 does not exert its physiological action due to the combination of rapid proteolytic degradation by ubiquitous dipeptidyldipeptidase IV (DPP IV) enzyme and renal clearance resulting in an extremely short circulating half-life. In this work we describe the conjugation of GLP-1-(7-36)-amide derivatives with polyethylene glycol (PEG) by enzymatic site-specific transglutamination reaction as an approach to reduce both the proteolysis and the renal clearance rates. The compound GLP-1-(7-36)-amide-Q23-PEG 20▒kDa monopegylated on the single glutamine residue naturally present in position 23 maintained the ability to activate the GLP-1 receptor expressed in the rat -cell line RIN-m5F with nanomolar potency along with an increased in vitro resistance to DDP IV and a circulating half-life of about 12▒h after subcutaneous administration in rats. These properties enabled GLP-(7-36)-amide-Q23-PEG 20▒kDa to exert a glucose-stabilizing effect for a period as long as 8▒h, as demonstrated by a si...
Source: Results in Pharma Sciences - Category: Drugs & Pharmacology Source Type: research