Proteases Functionalized Cyclopeptides

FIGURE 11.7 Structure of cyclopeptides c(Gly -Pi-oAba-5-CH2X) (9) and c(Gly -Pi-mAba-5-CH2X) (10). 

Another interesting target for this type of inhibitors is the dipeptidyl peptidase IV (DPP IV). This exodipeptidase, which can cleave peptides behind a proline residue is important in type 2 diabetes as it truncates the glucagon-like peptide 1. Taking into account the P2-Pi( Pro)-P,1 cleavage and the requirement for a free terminal amine, the synthesis of a suicide inhibitor was planned. It looked as if the the e-amino group of a P2 lysine residue could be cyclized because of the relative little importance of the nature of the P2 residue on the rate of enzymatic hydrolysis of known synthetic substrates. Therefore, anew series of cyclopeptides 11 was synthesized (Fig. 11.8). 

Molecules 11 rapidly and irreversibly inhibit the DPP IV activity of the CD26 antigen, with IC50 values in the nanomolar range. Cycle enlargement ( = 4 instead of 2) improves inhibitory activity, whereas increasing the alkyl chain length on the sulfur atom R has no apparent effect. Other aminopeptidases are not inhibited. Molecules 11 inhibit DPP I V-p, an isoform of DPP IV, much more poorly.32,56 

SCHEME 11.4 Postulated mechanism for inactivation of DPP IV by a functionalized cyclopeptide 11.32 

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