Highly potent and selective peptide-based inhibitors of the hepatitis C virus serine protease: towards smaller inhibitors |
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Authors: | Llinàs-Brunet M Bailey M Fazal G Ghiro E Gorys V Goulet S Halmos T Maurice R Poirier M Poupart M A Rancourt J Thibeault D Wernic D Lamarre D |
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Affiliation: | Boehringer Ingelheim, Canada Ltd, Research and Development, Laval, Quebec. mllinas@lav.boehringer-ingelheim.com |
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Abstract: | Structure-activity studies on a hexapeptide N-terminal cleavage product of a dodecamer substrate led to the identification of very potent and highly specific inhibitors of the HCV NS3 protease/NS4A cofactor peptide complex. The largest increase in potency was accomplished by the introduction of a (4R)-naphthalen-1-yl-4-methoxy substituent to the P2 proline. N-Terminal truncation resulted in tetrapeptides containing a C-terminal carboxylic acid, which exhibited low micromolar activity against the HCV serine protease. |
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