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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(More)
Significant advances have led to receptor induced-fit and conformational selection models for describing bimolecular recognition, but a more comprehensive view must evolve to also include ligand shape and conformational changes. Here, we describe an example where a ligand's "structural hinge" influences potency by inducing an "L-shape" bioactive(More)
(1R,2S)-1-Amino-2-vinylcyclopropanecarboxylic acid (vinyl-ACCA) is a key building block in the synthesis of potent inhibitors of the hepatitis C virus NS3 protease such as BILN 2061, which was recently shown to dramatically reduce viral load after administration to patients infected with HCV genotype 1. We have developed a scalable process that delivers(More)
The virally encoded NS5B RNA-dependent RNA polymerase has emerged as a prime target in the search for specific HCV antivirals. A series of benzimidazole 5-carboxamide compounds inhibit the cellular RNA replication of a HCV subgenomic replicon and we have advanced our understanding of this class of inhibitors through a combination of complementary approaches(More)
BACKGROUND 170 to 200 million people worldwide are believed to suffer from chronic hepatitis C virus (HCV) infection, a blood-born disease that targets the liver and progresses to organ cirrhosis and primary cancer in a significant proportion of patients. The currently available treatment has limited efficacy and suffers from restricting side effects. HCV(More)
Herpes simplex viruses (HSV) types 1 and 2 encode their own ribonucleotide reductases (RNRs) (EC 1.17.4.1) to convert ribonucleoside diphosphates into the corresponding deoxyribonucleotides. Like other iron-dependent RNRs, the viral enzyme is formed by the reversible association of two distinct homodimeric subunits. The carboxy terminus of the RNR small(More)
p56lck is a member of the src family of tyrosine kinases. Through modular binding units called SH2 domains, p56lck promotes phosphotyrosine-dependent protein-protein interactions and plays a critical role in signal transduction events that lead to T-cell activation. Starting from the phosphorylated dipeptide (2), a high-affinity ligand for the p56lck SH2(More)
It is known that peptides corresponding to the C-terminus of the small subunit of herpes simplex virus type 1 and 2 ribonucleotide reductase can inhibit enzymatic activity by preventing the association of the enzyme's two subunits. In a quest for smaller, more potent inhibitors, we have conducted a structure activity investigation based on the pentapeptide(More)
We have been investigating the potential of a new class of antiviral compounds. These peptidomimetic derivatives prevent association of the two subunits of herpes simplex virus (HSV) ribonucleotide reductase (RR), an enzyme necessary for efficient replication of viral DNA. The compounds disclosed in this paper build on our previously published work.(More)
BACKGROUND BILB 1941 is a potent and specific nonnucleoside inhibitor of the hepatitis C virus (HCV) RNA polymerase in vitro. METHODS In a double-blind sequential group comparison, 96 male HCV genotype 1 patients with minimal to mild liver fibrosis (Ishak or Metavir score 0-2) were randomized (8 to active treatment and 2 to placebo per dose group) and(More)