A new strategy for the development of highly potent and selective plasmin inhibitors.
ABSTRACT A new structure-based strategy for the design of potent and selective plasmin inhibitors was developed. These compounds could be prepared by cyclizations between the P3 and P2 amino acid residues of substrate-analogue inhibitors using metathesis or a copper-catalyzed azide alkyne cycloaddition in combination with standard peptide couplings. The most potent bis-triazole derivative 10 inhibits plasmin and plasma kallikrein with K(i) of 0.77 and 2.4 nM, respectively, whereas it has poor activity against the related trypsin-like serine proteases thrombin, factor Xa, or activated protein C. Modeling experiments revealed that inhibitor 10 adopts a compact and rigid structure that fits well into the relatively open active site of plasmin and plasma kallikrein, while it is rejected from sterically demanding residues present in loops of the other enzymes. These results from modeling confirm the selectivity profile found for inhibitor 10 in enzyme kinetic studies. Such compounds might be useful lead structures for the development of new antifibrinolytic drugs for use in cardiac surgery with cardiopulmonary bypass or organ transplantations to reduce bleeding complications.
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ABSTRACT: A series of new substrate analogue inhibitors of the WNV NS2B-NS3 protease containing decarboxylated arginine mimetics at the P1 position was developed. Among the various analogues, trans-(4-guanidino)cyclohexylmethylamide (GCMA) was identified as the most suitable P1 residue. In combination with dichloro-substituted phenylacetyl groups at the P4 position, three inhibitors with inhibition constants of <0.2 μM were obtained. These GCMA inhibitors have a better selectivity profile than the previously described agmatine analogues, and possess negligible affinity for the trypsin-like serine proteases thrombin, factor Xa, and matriptase. A crystal structure in complex with the WNV protease was determined for one of the most potent inhibitors, 3,4-dichlorophenylacetyl-Lys-Lys-GCMA (K(i) =0.13 μM). The inhibitor adopts a horseshoe-like conformation, most likely due to a hydrophobic contact between the P4 phenyl ring and the P1 cyclohexyl group, which is further stabilized by an intramolecular hydrogen bond between the P1 guanidino group and the P4 carbonyl oxygen atom. These inhibitors are stable, readily accessible, and have a noncovalent binding mode. Therefore, they may serve as suitable lead structures for further development.ChemMedChem 01/2013; · 2.84 Impact Factor
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ABSTRACT: Plasmin is best known as the key molecule in the fibrinolytic system, which is critical for clot lysis and can initiate matrix metalloproteinase (MMP) activation cascade. Along with MMP, plasmin is suggested to be involved in physiological processes that are linked to the risk of carcinoma formation. Plasmin inhibitors could be perceived as a promising new principle in the treatment of diseases triggered by plasmin. On the basis of the peptidic sequence derived from the synthetic plasmin substrate, a series of peptidic plasmin inhibitors possessing nitrile as warhead were prepared and evaluated for their inhibitory activities against plasmin and other serine proteases, plasma kallikrein and urokinase. The most potent peptidic inhibitors with the nitrile warhead exhibit the potency toward plasmin (IC(50) = 7.7-11 μM) and are characterized by their selectivity profile against plasma kallikrein and urokinase. The results and molecular modeling of the peptidic inhibitor complexed with plasmin reveal that the P2 residue makes favorable contacts with the open binding pocket comprising the S2 and S3 subsites of plasmin. Copyright © 2012 European Peptide Society and John Wiley & Sons, Ltd.Journal of Peptide Science 09/2012; 18(10):620-5. · 2.07 Impact Factor