F. George Njoroge

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We have been developing a series of nonpeptidic, small molecule farnesyl protein transferase inhibitors that share a common tricyclic nucleus and compete with peptide/protein substrates for binding to farnesyl protein transferase. Here, we report on pharmacological and in vivo studies with SCH 66336, a lead compound in this structural class. SCH 66336(More)
Recent work from this laboratory revealed that glucose-derived pyrroles can form with model amines under physiological conditions (Niroge, F. G., Sayre, L. M., and Monnier, V. M. (1987) Carbohydr. Res. 167, 211-220). The major extractable product, 5-hydroxymethyl-1-alkylpyrrole-2-carbaldehyde (named by us pyrraline) was labile to acid hydrolysis. To allow(More)
Cleavage of the hepatitis C virus (HCV) polyprotein by the viral NS3 protease releases functional viral proteins essential for viral replication. Recent studies by Foy and coworkers strongly suggest that NS3-mediated cleavage of host factors may abrogate cellular response to alpha interferon (IFN-alpha) (E. Foy, K. Li, R. Sumpter, Jr., Y.-M. Loo, C. L.(More)
Drug resistance is a major issue in the development and use of specific antiviral therapies. Here we report the isolation and characterization of hepatitis C virus RNA replicons resistant to a novel ketoamide inhibitor of the NS3/4A protease, SCH6 (originally SCH446211). Resistant replicon RNAs were generated by G418 selection in the presence of SCH6 in a(More)
An issue of clinical importance in the development of new antivirals for HCV is emergence of resistance. Several resistance loci to ketoamide inhibitors of the NS3/4A protease have been identified (residues V36, T54, R155, A156, and V170) by replicon and clinical studies. Using SCH 567312, a more potent protease inhibitor derived from SCH 503034(More)
The effect of the resistance mutations A156T, D168V, and D168Q in HCV protease on the binding of SCH 6, SCH 503034, VX-950, BILN-2061, and compound 1 was evaluated using the free energy perturbation (FEP) approach. All the inhibitors are highly potent against the wild-type enzyme, but their activity was affected differently by the mutants. A156T reduced the(More)
5-Hydroxyl-1-neopentylpyrrole-2-carbaldehyde, 2-(2-hydroxyacetyl)-1-neopentylpyrrole, in decreasing order or abundance, have been isolated and the structures characterized. These compounds were obtained from the reaction of a mixture of D-glucose and neopentylamine under physiological conditions of pH and temperature. In addition, 4H-dihydropyran-4-one, a(More)
More than 170 million people worldwide are affected by the hepatitis C virus (HCV). The disease has been described as a "silent epidemic" and "a serious global health crisis". HCV infection is a leading cause of chronic liver disease such as cirrhosis, carcinoma, or liver failure. The current pegylated interferon and ribavirin combination therapy is(More)
The structure of the metalloproteinase and hemorrhagic toxin atrolysin C form d (EC 3.4.24.42), from the venom of the western diamondback rattlesnake Crotalus atrox, has been determined to atomic resolution by x-ray crystallographic methods. This study illuminates the nature of inhibitor binding with natural (< Glu-Asn-Trp, where < Glu is pyroglutamic acid)(More)
HCV NS3 serine protease mediates the cleavage of the HCV polyprotein to release the functional proteins that are essential for viral propagation. The inhibition of NS3 protease activity is expected to block HCV replication in infected host cells, and therefore protease inhibitors are a potential new treatment strategy for HCV. Several novel HCV protease(More)