Dipeptidyl peptidase IV (DPP-IV) from pig kidney cleaves analogs of bovine growth hormone-releasing factor (bGRF) modified at position 2 with Ser, Thr or Val. Extended DPP-IV substrate specificity?

Dipeptidyl peptidase IV resistant analogues of glucagon-like peptide-1 which have extended metabolic stability and improved biological activity

“…Accordingly, the in vitro t 1/2 of the GLP-1 analogues were considerably extended relative to GLP-1 (7± 36) amide. There was no detectable degradation of the Aib 8 analogue, and the slow degradation of the other three analogues could reflect the substrate specificity of DPP IV, as was found for GRF; substitution of the alanine in position 2 of modified GRF analogues with either serine or threonine reduced the cleavage rates to less than 5 %, of that of the Ala 2 analogue [20]. That DPP IV is also the main enzyme responsible for in vivo N-terminal degradation of GLP-1 is illustrated by the increased proportions of N-terminal immunoreactivity (reflecting intact peptide) seen during i. v. infusion of each analogue relative to GLP-1 itself, and confirmed by HPLC analysis which revealed only two immunoreactive peaks corresponding to the intact peptide and the N-terminally truncated metabolite.…”

“…DPP IV is highly specific and has strict substrate requirements [18,19], raising the possibility of developing analogues which the enzyme is unable to cleave. Studies with another peptide substrate of DPP IV, growth hormone-releasing factor (GRF), have shown that analogues with N-terminal amino acid substitutions have some resistance to the enzyme's action [20]. The present study was undertaken to examine whether small modifications of the N-terminus of GLP-1 would also confer resistance to degradation by DPP IV, while retaining the peptide's biological activity.…”

Implications of DPP4 modification of proteins that regulate stem/progenitor and more mature cell types

“…However, some reports suggest that additional residues in the penultimate position, such as serine, could also be targets of DPP4, but these sites are considered less preferred than the proline or alanine. 9 Importantly, certain protein modifications can alter the rate of cleavage. Proteins with proline, hydroxylproline, or N-methylglycine in the third position are thought to prevent cleavage by DPP4.…”

“…9 DPP4 is found as both a type II cell surface protein (CD26) and as a soluble molecule lacking intracellular and transmembrane domains.…”

Smac-Derived Aza-Peptide As an Aminopeptidase-Resistant XIAP BIR3 Antagonist

“…Although DPP-IV is an N-terminal dipeptidyl peptidase that can cleave a dipeptide unit in 'one bite' from longer peptides with Val at the P2 position [29], it might have been expected that all the three Smac-derived peptides (1), (2) and (9) would have been subject to degradation by this peptidase (they all have Val at P2). However, the presence of Pro at P3 makes all of the N-terminal Smac-derived sequences intrinsically resistant to DPP-IV, since peptides with Pro at P3 are known to function as DPP-IV inhibitors [30].…”