Small-molecule inhibitor: PPACK

Name

History: PPACK was first described by Kettner & Shaw (1979).
Peptidases inhibited: Thrombin is inhibited with high selectivity. At high concentration (5 micromolar) PPACK also inhibits coagulation factor XIIa: Silverberg & Kaplan, 1982) and batroxobin (Sturzebecher et al., 1986).
Mechanism: Inhibition is irreversible. The mode of binding has been demonstrated crystallographically (Bode et al., 1989; Bode et al., 1992). The inhibitor is bound to the active site Ser and His sidechains, and the inhibitor backbone forms an anti-parallel beta-sheet interaction with the backbone of the peptidase.
Pharmaceutical relevance: As a chloromethane, PPACK is likely to be too reactive to be used as a drug, but it has been used in clinical chemistry as a selective reagent for the inhibition of thrombin in blood samples (Lyon et al., 1999).

Inhibitor class: This compound is of the halomethylketone class of serine peptidase inhibitors. Such compounds are activated ketones that form tetrahedral adducts with serine peptidases. On the basis of detailed studies with several serine peptidases it seems that a Michaelis complex is formed intially, and then a hemiketal is formed by attack of the active site serine on the carbonyl carbon of the inhibitor. The hemiketal still contains the halide. When the halide is chlorine rather than fluorine the reaction may proceed to alkylation of the ring of the active site His, with liberation of the chlorine (Powers, 1977). The halomethylketones have been reviewed by Powers et al. (2002), pp. 4646 - 4656.