D-phe-Pro-Arg-chloromethyl ketone

A group of peptide derivatives such as peptide arginals and boronic acid peptide derivatives belong to another class of reversible thrombin inhibitors. One such inhibitor is PPACK (D-Phe-Pro-Arg chloromethyl ketone), which functions as a powerful irreversible thrombin inhibitor by alkylating the histidine residue at the catalytic site of thrombin (58). It, however, is unstable in neutral solution, as it undergoes cyclization and inactivation. However, the D-methyl derivative of D-Phe-Pro-Arg-H (D-Mephe-Pro-Arg-H) called efegatran, with a molecular mass of 515 Da, is a stable selective reversible inhibitor of thrombin with a K. of approximately 100 nM. The basic amino terminus in this compound is responsible for promoting the specificity toward thrombin (63). 

Following the initial structure determination of D-Phe-Pro-Arg chloromethyl ketone-inhibited human a-fhrombin [25], the structures of more than 100 thrombin complexes have been solved and deposited in the Protein Data Bank. In addition, a number of prothrombin fragments and intermediates, the three-dimensional structure of the immediate precursor of a-thrombin, prethrombin-2 (pre-cleavage cat-... 

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