N-TERMINALACETYLATIONPROTECTSGLUCAGON-LIKEPEPTIDE GLP-1-(7-34)-AMIDEFROMDPP-IV-MEDIATEDDEGRADATION RETAININGCAMP- ANDINSULIN-RELEASINGCAPACITY

Since its discovery glucagon-like peptide-1 (GLP-1) is investigated as a treatment for type II dia- betes based on its major function as insulin secreta- gogue. A therapeutic use is, however, limited by its short biological half-life in the range of minutes, pre- dominantly caused via degradation catalyzed by dipep- tidyl peptidase IV (DPP-IV). Therefore, we aimed to design a GLP-1 analogue exhibiting resistance against DPP-IV-catalyzed inactivation while retaining its bi- ologiocal activity. By means of matrix-assisted laser desorption/ionization mass spectrometry (MALDI MS) we have studied the stability of the N-terminally blocked new analogue Ac-GLP-1-(7-34)-amide against DPP-IV and compared it with both unblocked GLP- 1-(7-34)-amide and the major naturally occurring form GLP-1-(7-36)-amide. GLP-1-(7-36)-amide and the C- terminally two amino acid residues shorter GLP-1-(7- 34)-amide rapidly generated peptide fragments trun- cated by the N-terminal dipeptide. In contrast, the N- terminal blocked Ac-GLP-1-(7-34)-amide was not de- graded in the presence of DPP-IV over a period of at least two hours. Ac-GLP-1-(7-34)-amide induced a concentration-dependent increase of intracellular cAMP production and insulin release from rat insuli- noma RIN-m5F cells to an extent comparable to that found for the N-terminally unblocked peptides GLP- 1-(7-34)-amide and GLP-1-(7-36)-amide. Ac-GLP-1- (7-34)-amide may thus have the potential to act as a new long-acting GLP-1 analogue with significant resis- tance against DPP-IV and retained biological activity in vitro. Further research is required to investigate whether Ac-GLP-1-(7-34)-amide also exhibits its char- acteristics in animal models and humans.