BIOL 126 |
| A structure-activity relationship (SAR) for reversible inhibitory activity toward thrombin of tetrapetides from series D-Phe-Pro-DArg-P1'-CONH2 is reported. The P1' position was varied with D and L amino acids. The significant differences between the inhibitory constants (Kis) of tetrapeptides from the series D-Phe-Pro-D-Arg-P1'-CONH2 suggest that the interaction between the amino acid at P1' position and the S1' subpocket in thrombin is very specific. There is a 2 to 500 fold experimentally determined difference between the Kis of different peptide inhibitors and our in vitro inhibition assay for thrombin proved that the P1' position requires small and polar amino-acids. Functional assays, such as thrombin-induced platelets aggregation confirmed that the peptides were effective in inhibiting the platelets aggregation completely at concentration 10-15 fold their Ki determined from in vitro inhibition of thrombin. The aggregation of platelets by some lead peptides was specific only for thrombin-induced platelets aggregation, since there was no inhibition of platelets aggregation in the presence of another agonist for activation of such as collagen. These results strongly support our original structure-based design of peptides as reversible inhibitors for thrombin. |
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Chemistry and Metabolism
4:30 PM-6:30 PM, Tuesday, 12 September 2006 Moscone Center -- Hall D, Poster
Division of Biological Chemistry |