AEI 14 |
| The major goal of this investigation was to perform a structure-based design and lead optimization of tetrapeptides that can reversibly inhibit thrombin. We focused on tetrapeptides with the sequence space (NH2)-DPhe (P3)–Pro (P2)–DArg (P1)-P1'-CONH2 which was shown previously to inhibit thrombin in vitro. F-moc manual synthesis of amide-tetrapeptide libraries was performed on a Rink-Amide resin incorporating phenylalanine (Phe) analogs in the P3 position such as trans/(cis) cinnamic, dihydrocinnamic acids, D-Naphthylalanine (DNal), Phe constrained analog 1,2,3,4- (D)-tetrahydroisoquinoline-3-carboxylic acid [(D) Tic], D-3,5-difluorophenylalanine and 1,2,3,4-tetrahydronorharman-3-carboxylic acid. The libraries were obtained using the partition-mixing procedure coupled with parallel synthesis. Ten variation in the P1' position were performed using natural and un-natural amino-acids that were shown very good inhibitory activity for thrombin in the sequence space DPhe (P3)–Pro (P2)–DArg-P1', i.e. P1' = D-Ser, D-Cys, D-Ala, L/D-Thi, D-3-benzothienylalanine, D-His, D-Pro, D-Thr, D-Asn and D-Gln. Preliminary results showed that replacement of D-Phe in P3 position with D-Nal had a two fold increased inhibitory activity for thrombin in an in vitro assay competing with the chromogenic substrate S2238. Compounds having the experimentally determined inhibitory constant (Ki) between 16.5 –0.8 uM are potential competitive inhibitors. |
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Academic Employment Initiative
8:00 PM-10:00 PM, Monday, August 20, 2007 BCEC -- Exhibit Hall - B2, Sci-Mix
Academic Employment Initiative |