An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus

Hepatitis C virus (HCV) infection is a serious cause of chronic liver disease worldwide with more than 170 million infected individuals at risk of developing significant morbidity and mortality. Current interferon-based therapies are suboptimal especially in patients infected with HCV genotype 1, and they are poorly tolerated, highlighting the unmet medical need for new therapeutics. The HCV-encoded NS3 protease is essential for viral replication and has long been considered an attractive target for therapeutic intervention in HCV-infected patients. Here we identify a class of specific and potent NS3 protease inhibitors and report the evaluation of BILN 2061, a small molecule inhibitor biologically available through oral ingestion and the first of its class in human trials. Administration of BILN 2061 to patients infected with HCV genotype 1 for 2 days resulted in an impressive reduction of HCV RNA plasma levels, and established proof-of-concept in humans for an HCV NS3 protease inhibitor. Our results further illustrate the potential of the viral-enzyme-targeted drug discovery approach for the development of new HCV therapeutics.     

Phenotypic changes induced by a mutated ras gene during the development of Dictyostelium transformants

The ras proto-oncogene, found in all eukaryotes so far examined, encode s a protein with guanine nucleotide-binding and GTPase activity. Gene disruption experiments in yeast indicate that ras is essential for cell growth. Anit-sense mutagenesis approaches suggest that this is also true for Dictyostelium. Most mutations causing an amino-acid substitution for Gly 12 result in decreased GTPase activity and produce a transforming phenotype. In yeast, a Gly 19---- Val 19, missense mutation (Gly 19 is similar to Gly 12 in mammalian and Dictyostelium ras proteins) causes a series of dominant phenotypes, including elevated adenylate cyclase activity. In mammalian cells there is no evidence that ras activates adenylate cyclase activity. D. discoideum contains a single ras gene (Dd-ras) that encodes a protein very similar to the mammalian ras protein and identical to c-ras at the potentially transforming positions. Dd-ras is expressed in vegetative cells and later in development in prestalk cells whereas ras protein is found in vegetative and developing cells. In the migrating pseudoplasmodium, ras protein is found in prestalk but not prespore cells, suggesting it is involved in the function and/or differentiation of the anteriorly localized prestalk cells. In this report we examine the effects of expression of a Dd-ras gene carrying a Gly-12----Thr 12 missense mutation.