The major goal of this investigation was to perform a structure-based design and lead optimization of tetrapeptides that can reversibly inhibit thrombin. We were focusing 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], and 1,2,3,4-tetrahydronorharman-3-carboxylic acid. The libraries were obtained using the partition-mixing procedure coupled with parallel synthesis. 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.
Back to Organic Posters
Back to The 37th Middle Atlantic Regional Meeting (May 22-25, 2005)