A5091414363- Hepatitis C virus research
- HIV/AIDS drug development and treatment
- Herpesvirus Infections and Treatments
- Crystallization and Solubility Studies
- Hepatitis B Virus Studies
- X-ray Diffraction in Crystallography
- Toxin Mechanisms and Immunotoxins
- Virus-based gene therapy research
- Monoclonal and Polyclonal Antibodies Research
- Cytomegalovirus and herpesvirus research
- Viral-associated cancers and disorders
- Click Chemistry and Applications
- Biochemical and Molecular Research
- Bacteriophages and microbial interactions
- HIV Research and Treatment
- Poxvirus research and outbreaks
- Chemical Synthesis and Analysis
- Liver Disease Diagnosis and Treatment
- Cancer-related Molecular Pathways
- Plant Disease Resistance and Genetics
- Insect and Pesticide Research
- Chronic Lymphocytic Leukemia Research
- Food Allergy and Anaphylaxis Research
- Systemic Lupus Erythematosus Research
- Virology and Viral Diseases
Bristol-Myers Squibb (United States)
1996-2018
Bristol-Myers Squibb (Germany)
1995-2014
UConn Health
1997
ABSTRACT Asunaprevir (ASV; BMS-650032) is a hepatitis C virus (HCV) NS3 protease inhibitor that has demonstrated efficacy in patients chronically infected with HCV genotype 1 when combined alfa interferon and/or the NS5A replication complex daclatasvir. ASV competitively binds to NS3/4A complex, K i values of 0.4 and 0.24 nM against recombinant enzymes representing genotypes 1a (H77) 1b (J4L6S), respectively. Selectivity was by absence any significant activity closely related GB virus-B...
ABSTRACT Asunaprevir (BMS-650032) is a potent hepatitis C virus (HCV) NS3 protease inhibitor demonstrating efficacy in alfa interferon-sparing, direct-acting antiviral dual-combination regimens (together with the NS5A replication complex daclatasvir) patients chronically infected HCV genotype 1b. Here, we describe comprehensive vitro genotypic and phenotypic analysis of asunaprevir-associated resistance against genotypes 1a 1b using replicons patient samples obtained from clinical studies...
The discovery of asunaprevir (BMS-650032, 24) is described. This tripeptidic acylsulfonamide inhibitor the NS3/4A enzyme currently in phase III clinical trials for treatment hepatitis C virus infection. 24 was enabled by employing an isolated rabbit heart model to screen cardiovascular (CV) liabilities (changes HR and SNRT) that were responsible discontinuation earlier lead from this chemical series, BMS-605339 (1), trials. structure–activity relationships (SARs) developed with respect CV...
ABSTRACT Packaging of DNA into preformed capsids is a fundamental early event in the assembly herpes simplex virus type 1 (HSV-1) virions. Replicated viral genomes, form complex branched concatemers, and unstable spherical precursor termed procapsids are thought to be substrates for DNA-packaging reaction. In addition, seven proteins required packaging, although their individual functions undefined. By analogy well-characterized bacteriophage systems, association these with various forms...
ABSTRACT Herpes simplex virus type 1 (HSV-1) capsid proteins assemble in vitro into spherical procapsids that differ markedly structure and stability from mature polyhedral capsids but can be converted to the form. Circumstantial evidence suggests assembly vivo follows a similar pathway of procapsid maturation, resembles those double-stranded DNA bacteriophages. We have confirmed above by isolating HSV-1-infected cells characterizing their morphology, thermal sensitivity, protein...
The discovery of BMS-605339 (35), a tripeptidic inhibitor the NS3/4A enzyme, is described. This compound incorporates cyclopropylacylsulfonamide moiety that was designed to improve potency carboxylic acid prototypes through introduction favorable nonbonding interactions within S1′ site protease. identification 35 enabled optimization and balance critical properties including pharmacokinetics (PK). achieved modulation P2* subsite which identified isoquinoline ring system as key template for...
Hepatitis C virus (HCV) protease inhibitors combined with pegylated alfa interferon-ribavirin have demonstrated improved efficacy compared alone for the treatment of chronic hepatitis C. Asunaprevir (BMS-650032), a novel HCV NS3 inhibitor in clinical development, was evaluated safety, antiviral activity, and resistance four double-blind, placebo-controlled, sequential-panel, single- multiple-ascending-dose (SAD MAD) studies healthy subjects or genotype 1 infection. In SAD studies, (healthy...
The clinical efficacy of a pegylated form human lambda 1 interferon (IFN-λ1; also referred to herein as lambda) has been demonstrated in patients chronically infected with hepatitis C virus (HCV) representing genotypes through 4. In these proof-of-concept studies, showed an improved safety profile compared the alpha (referred alfa). study described this report, assessment vitro antiviral activity type III IFNs toward different HCV replicons revealed that unpegylated recombinant IFN-λ1...
ABSTRACT Herpes simplex virus (HSV) DNA is cleaved from concatemers and packaged into capsids in infected cell nuclei. This process requires seven viral proteins, including UL15 UL28. expressed alone displays a nuclear localization, while UL28 remains cytoplasmic. Coexpression with enables to enter nuclei, suggesting an interaction between the two proteins. Additionally, copurified HSV-infected cells after ion-exchange affinity chromatography, complex sedimented as 1:1 heterodimer upon...
The herpes simplex virus type 1 (HSV-1) UL15 gene is a spliced composed of two exons and predicted to encode an 81-kDa protein 735 amino acids (aa). Two products with molecular masses 75 35 kDa have been observed (J. Baines, A. Poon, J. Rovnak, B. Roizman, Virol. 68:8118-8124, 1994); however, it not clear whether the smaller form represents proteolytic cleavage product larger or separately translated. In addition, HSV-1 temperature-sensitive mutant in (ts66.4) defective both viral DNA...
The design and synthesis of potent, tripeptidic acylsulfonamide inhibitors HCV NS3 protease that contain a difluoromethyl cyclopropyl amino acid at P1 are described. A cocrystal structure 18 with NS3/4A complex suggests the presence H-bond between polarized C-H CHF2 moiety backbone carbonyl Leu135 enzyme. Structure-activity relationship studies indicate this enhances enzyme inhibitory potency by 13- 17-fold compared to CH3 CF3 analogues, respectively, providing insight into deployment unique acid.
The discovery of a back-up to the hepatitis C virus NS3 protease inhibitor asunaprevir (2) is described. objective this work was identification drug with antiviral properties and toxicology parameters similar 2, but preclinical pharmacokinetic (PK) profile that predictive once-daily dosing. Critical process employment an ex vivo cardiovascular (CV) model which served identify compounds that, like were free CV liabilities resulted in discontinuation BMS-605339 (1) from clinical trials....
Herpes simplex virus type 1 (HSV-1) capsids are initially assembled with an internal protein scaffold. The scaffold proteins, encoded by overlapping in-frame UL26 and UL26.5 transcripts, essential for formation efficient maturation of capsids. encodes N-terminal protease domain, its C-terminal oligomerization capsid protein-binding domains identical to those UL26.5. cleaves itself, releasing minor proteins VP24 VP21, the more abundant protein, major VP22a. Unlike VP21 VP22a, which removed...
Lobucavir (LBV) is a deoxyguanine nucleoside analog with broad-spectrum antiviral activity. LBV was previously shown to inhibit herpes simplex virus (HSV) DNA polymerase after phosphorylation by the HSV thymidine kinase. Here we determined mechanism of action against human cytomegalovirus (HCMV). inhibited HCMV synthesis degree comparable that ganciclovir (GCV), drug known target viral polymerase. The expression late proteins and RNA, dependent on synthesis, also LBV. Immediate-early early...
To support clinical development of HCV non-structural protein (NS) 3 protease inhibitors (PIs), phenotypic monitoring patient isolates is a prerequisite for understanding the emergence resistance. typically fail to replicate in cell culture, necessitating use alternative phenotyping methods.An NS3 chimeric replicon system was developed monitor phenotype isolates. The transfer domain sequences from HCV-infected patients background genotype (Gt) 1a-H77c, 1b-Con1 and 2a-JFH-1 lab strain...
A series of novel aminodiol inhibitors HIV protease based on the lead compound 1 with structural modifications at P1' were synthesized in order to reduce cytotoxicity 1. We have observed a high degree correlation between lipophilicity and this inhibitors. It was found that appropriate substitution para position phenyl group resulted identification equipotent (both against enzyme cell culture) compounds (10l, 10m, 10n, 15c) which possess significantly decreased cytotoxicity.
The human cytomegalovirus (HCMV) UL98 gene is predicted to encode a homologue of the conserved herpesvirus alkaline nuclease. To determine if HCMV product functionally homologous other nucleases, protein was purified and its activity characterized in vitro. Extracts HCMV-infected cells were fractionated using Q Sepharose, phos- phocellulose native DNA cellulose chromatography. immunoreactivity copurified with pH-dependent nuclease activity. migrated at size approximately 65 kDa denaturing...
A phenotypic high-throughput cell culture screen was performed to identify compounds that prevented proliferation of the human Papilloma virus type 16 (HPV-16) transformed line Ca Ski. series quinoxaline exemplified by Compound 1 identified. Testing against a panel lines demonstrated selectively inhibited replication all HPV-16, HPV-18, and HPV-31 tested with 50% Inhibitory Concentration (IC50) values 2 8 μM relative IC50 28 73 in HPV-negative lines. Treatment resulted cascade multiple...
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