Modulation of procarboxypeptidase R (ProCPR) activation by complementary peptides to thrombomodulin

We designed complementary peptides (C-peptides) using a novel computer program (MIMETIC), which generates a series of peptides designed to interact with a target peptide sequence. Carboxypeptidase R (CPR) is an unstable basic carboxypeptidase found in fresh serum in addition to carboxypeptidase N (CPN) which is stable. CPR is generated from its precursor form (proCPR) by trypsin-like enzymes, and its activation is mediated by thrombin generated in the coagulation cascade. The efficiency of activation is enhanced approximately 1,200-fold when thrombin (T) is bound to thrombomodulin (TM). We attempted to generate C-peptides which recognize the T-binding site within TM assuming that some of these might interfere with the generation of T and TM complexes (T-TM). Among three peptides designed, two inhibited the enhancement in activation of proCPR by T in the presence of TM. One of the peptides at 16 microM reduced the activation of proCPR to the level obtained by T alone.