A5058806897- Hepatitis C virus research
- Hepatitis B Virus Studies
- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Liver Disease Diagnosis and Treatment
- Monoclonal and Polyclonal Antibodies Research
- Bacteriophages and microbial interactions
- Viral Infections and Outbreaks Research
- Animal Virus Infections Studies
- Synthesis and Catalytic Reactions
- Synthetic Organic Chemistry Methods
- HIV Research and Treatment
- Plant Virus Research Studies
- Carbon dioxide utilization in catalysis
- Metal complexes synthesis and properties
- Immunodeficiency and Autoimmune Disorders
- RNA regulation and disease
- Asymmetric Hydrogenation and Catalysis
- Immunotherapy and Immune Responses
- Malaria Research and Control
- Cancer-related gene regulation
- Mosquito-borne diseases and control
- Viral gastroenteritis research and epidemiology
- Carbohydrate Chemistry and Synthesis
- Thyroid Disorders and Treatments
Janssen (Belgium)
2013-2024
Johnson & Johnson (United States)
2017-2018
Kyushu University
2013
University of Freiburg
2005-2008
University Hospital of Lausanne
2005-2008
University of Lausanne
2005-2008
University Medical Center Freiburg
2005
Vrije Universiteit Amsterdam
1978
University of Amsterdam
1978
TMC435 is a small-molecule inhibitor of the NS3/4A serine protease hepatitis C virus (HCV) currently in phase 2 development. The vitro resistance profile was characterized by selection experiments with HCV genotype 1 replicon cells and 2a JFH-1 system. In 80% (86/109) sequences from analyzed, mutation at NS3 residue D168 observed, changes to V or A being most frequent. Mutations positions 43, 80, 155, 156, alone combination, were also identified. transient assay confirmed relevance these for...
ABSTRACT Hepatitis B virus (HBV) capsid assembly is a critical step in the propagation of and mediated by core protein. Due to its multiple functions viral life cycle, became an attractive target for new antiviral therapies. Capsid modulators (CAMs) accelerate kinetics prevent encapsidation polymerase-pregenomic RNA (Pol-pgRNA) complex, thereby blocking replication. CAM JNJ-632 novel potent inhibitor HBV replication vitro across genotypes A D. It induces formation morphologically intact...
The assembly of hepatitis B virus (HBV) core protein (HBc) into capsids represents a critical step viral replication. HBc has multiple functions during the HBV life cycle, which makes it an attractive target for antiviral therapies. Capsid modulators (CAMs) induce formation empty capsid or aberrant devoid pregenomic RNA (pgRNA) and finally block relaxed circular DNA neosynthesis virion progeny. In this study, novel CAMs JNJ-827 JNJ-890 were found to be potent inhibitors replication with...
Hepatitis C virus (HCV) NS3-4A is a membrane-associated multifunctional protein harboring serine protease and RNA helicase activities. It an essential component of the HCV replication complex prime target for antiviral intervention. Here, we show that membrane association structural organization are ensured in cooperative manner by two membrane-binding determinants. We demonstrate N-terminal 21 amino acids NS4A form transmembrane alpha-helix may be involved intramembrane protein-protein...
Capsid assembly is a critical step in the hepatitis B virus (HBV) life cycle, mediated by core protein. Core potential target for new antiviral therapies, capsid modulators (CAMs). JNJ-56136379 (JNJ-6379) novel and potent CAM currently phase II trials. We evaluated mechanisms of action (MOAs) properties JNJ-6379 vitro Size exclusion chromatography electron microscopy studies demonstrated that induced formation morphologically intact viral capsids devoid genomic material (primary MOA)....
Hepatitis C virus (HCV) is a major cause of chronic liver disease, cirrhosis, and hepatocellular carcinoma worldwide. HCV has positive-strand RNA genome about 9.4 kb in size, which serves as template for replication translation polyprotein 3,000 amino acids. The cleaved co- posttranslationally by cellular viral proteases into at least 10 different mature proteins. One these proteins, nonstructural protein 3 (NS3), serine protease NTPase/RNA helicase activity. Arginine 467 the domain NS3...
Small molecule induced hepatitis B virus (HBV) capsid assembly modulation is considered an attractive approach for new antiviral therapies against HBV. Here we describe efforts toward the discovery of a HBV modulator in hit-to-lead optimization, resulting JNJ-632, tool compound used to further profile mode action. Administration JNJ-632 (54) genotype D infected chimeric mice resulted 2.77 log reduction DNA viral load.
Abstract Hepatitis B virus (HBV) capsid assembly modulators (CAMs) represent a recent class of anti-HBV antivirals. CAMs disturb proper nucleocapsid assembly, by inducing formation either aberrant assemblies (CAM-A) or apparently normal but genome-less empty capsids (CAM-E). Classical structural approaches have revealed the CAM binding sites on protein (Cp), conformational information CAM-induced off-path is lacking. Here we show that solid-state NMR can provide such information, including...
Capsid assembly is critical in the hepatitis B virus (HBV) life cycle, mediated by viral core protein. target for new anti-viral therapeutics known as capsid modulators (CAMs) of which CAM-aberrant (CAM-A) class induces aberrant shaped protein structures and leads to hepatocyte cell death. This study aimed identify mechanism action CAM-A leading HBV-infected elimination where CAM-A-mediated surface antigen (HBsAg) reduction was evaluated a stable HBV replicating line AAV-HBV-transduced...
The current therapy for hepatitis C virus (HCV) infection has limited efficacy, in particular against the genotype 1 virus, and a range of side effects. In this context high unmet medical need, more efficacious drugs targeting HCV nonstructural proteins are interest. Here we describe 2'-deoxy-2'-spirocyclopropylcytidine (5) as new inhibitor NS5B RNA-dependent RNA polymerase, displaying an EC(50) 7.3 μM measured Huh7-Rep cell line no associated cytotoxicity (CC(50) > 98.4 μM). Computational...
Hepatitis C virus (HCV) infection is a major global health burden and associated with an increased risk of liver cirrhosis hepatocellular carcinoma. There remains unmet medical need for efficacious safe direct antivirals complementary modes action combination in treatment regimens to deliver high cure rate short duration HCV patients. Here we report the vitro inhibitory activity, mode action, binding kinetics, resistance profile TMC647055, novel potent nonnucleoside inhibitor NS5B...
The limited efficacy, in particular against the genotype 1 virus, as well variety of side effects associated with current therapy for hepatitis C virus (HCV) infection necessitates more efficacious drugs. We found that phosphoramidate prodrugs 2'-deoxy-2'-spirooxetane ribonucleosides form a novel class HCV NS5B RNA-dependent RNA polymerase inhibitors, displaying EC50 values ranging from 0.2 to >98 μM, measured Huh7-replicon cell line, no apparent cytotoxicity (CC50 > 98.4 μM). Confirming...
The RNA-dependent RNA polymerase (NS5B) of hepatitis C virus (HCV) is an unusually attractive target for drug discovery since it contains five distinct drugable sites. success novel antiviral therapies will require nonnucleoside inhibitors to be active in at least patients infected with HCV subtypes 1a and 1b. Therefore, the genotypic assessment these agents against clinical isolates derived from genotype 1-infected important prerequisite selection suitable candidates development. Here we...
Structure-based macrocyclization of a 6-carboxylic acid indole chemotype has yielded potent and selective finger-loop inhibitors the hepatitis C virus (HCV) NS5B polymerase. Lead optimization in conjunction with vivo evaluation rats identified several compounds showing (i) nanomolar potency HCV replicon cells, (ii) limited toxicity off-target activities, (iii) encouraging preclinical pharmacokinetic profiles characterized by high liver distribution. This effort culminated identification...
To characterize antiviral activity of the capsid assembly modulator (CAM-N) JNJ-56136379 against HBV genotypes and variants carrying amino acid substitutions in core protein.Anti-HBV was investigated a diverse panel 53 clinical isolates (genotypes A-H). The impact using site-directed mutants (SDMs) assessed transient replication assay.JNJ-56136379 median 50% effective concentration (EC50) values across all were 10-33 nM versus 17 (genotype D reference). remained active nucleos(t)ide analogue...
Modulation of capsid assembly by small molecules has become a central concept in the fight against viral infection. Proper is crucial to form high molecular weight structures that protect genome and that, often concert with envelope, allow for cell entry fusion. Atomic details underlying modulation are generally studied using preassembled protein complexes, while activity modulators during remains largely open poorly understood, as necessary tools lacking. We here use full-length hepatitis B...
Viruses have evolved strategies to overcome the antiviral effects of host at different levels. Besides specific defence mechanisms, responds viral infection via interferon pathway and also by RNA interference (RNAi). However, several viruses been identified that suppress RNAi. We addressed question whether hepatitis C virus (HCV) suppresses RNAi, using cell lines constitutively expressing green fluorescent protein (GFP) inducibly HCV proteins. It was found short interfering RNA-mediated GFP...
JNJ-54257099 (9) is a novel cyclic phosphate ester derivative that belongs to the class of 2'-deoxy-2'-spirooxetane uridine nucleotide prodrugs which are known as inhibitors HCV NS5B RNA-dependent RNA polymerase (RdRp). In Huh-7 genotype (GT) 1b replicon-containing cell line 9 devoid any anti-HCV activity, an observation attributable inefficient prodrug metabolism was found be CYP3A4-dependent. contrast, in vitro incubation primary human hepatocytes well pharmacokinetic evaluation thereof...
Four weeks of once-daily oral JNJ-56136379 (JNJ-6379; 25, 75, 150 or 250 mg), a class-N capsid assembly modulator (CAM-N), was well tolerated with potent antiviral activity in treatment-naïve, chronic hepatitis B e antigen-positive and antigen-negative patients (NCT02662712). Hepatitis virus (HBV) genome sequence analysis, using HBV DNA next-generation technology, performed, impact substitutions on efficacy assessed. Analyses focused core protein amino acid positions associated JNJ-6379...