Peptidomimetic inhibitors for activated protein C: implications for hemophilia management.
BACKGROUND
Several clinical studies and experiments with transgenic mice have suggested that the severity of the bleeding phenotype in hemophilic patients is substantially reduced in association with impaired inactivation of factor (F) Va by activated protein C (APC) in the presence of the FV Leiden mutation. Experiments using a synthetic coagulation proteome model showed that the presence of FV Leiden significantly increased thrombin generation in the absence of FVIII or FIX.


OBJECTIVE
To test the effect of APC inhibition on thrombin generation in hemophilia.


METHODS
Prothrombinase and a synthetic coagulation proteome model of tissue factor-triggered thrombin generation were used.


RESULTS
Peptide-based APC inhibitors, which mimic the P4-P4' residues surrounding the APC cleavage site at Arg306 of FVa, were synthesized. These compounds are specific and reversible inhibitors of APC, with Ki values as low as 1-2 microM; most have insignificant affinity for FXa or thrombin. The affinity for APC is dependent upon the location and character of the protecting groups. Representatives of this group of compounds inhibit FVa inactivation by APC and prolong FVa functional activity in the prothrombinase complex. When evaluated in a synthetic coagulation proteome model, one inhibitor partially compensated for the absence of FVIII.


CONCLUSIONS
Synthetic APC inhibitors may be useful as adjuvants for hemophilia treatment.
Butenas
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S
Department of Biochemistry, University of Vermont, Colchester, VT 05446, USA. sbutenas@uvm.edu
Orfeo
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Kalafatis
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Mann
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D020016:Activated Protein C Resistance / Q000188:drug therapy* / Q000201:enzymology; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests / Q000379:methods; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000627:therapeutic use; D005165:Factor V / Q000378:metabolism; D015943:Factor Va / Q000378:metabolism; D015951:Factor Xa / Q000378:metabolism; D006467:Hemophilia A / Q000188:drug therapy* / Q000201:enzymology; D006801:Humans; D008954:Models, Biological; D011486:Protein C / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D020543:Proteome / Q000737:chemistry / Q000378:metabolism
D004791:Enzyme Inhibitors; D011486:Protein C; D020543:Proteome; C095381:factor V Leiden; C022475:prothrombinase complex; D015943:Factor Va; D005165:Factor V; D015951:Factor Xa