A5079927678- Hepatitis C virus research
- HIV/AIDS drug development and treatment
- Hepatitis B Virus Studies
- Viral Infections and Immunology Research
- Cancer therapeutics and mechanisms
- Plant Virus Research Studies
- Biochemical and Molecular Research
- RNA and protein synthesis mechanisms
- Monoclonal and Polyclonal Antibodies Research
- Liver Disease Diagnosis and Treatment
- DNA Repair Mechanisms
- DNA and Nucleic Acid Chemistry
- ATP Synthase and ATPases Research
- Plant Disease Resistance and Genetics
- Synthesis and Biological Evaluation
- Chronic Lymphocytic Leukemia Research
- RNA Research and Splicing
- HIV Research and Treatment
- CRISPR and Genetic Engineering
- Mechanisms of cancer metastasis
- Carcinogens and Genotoxicity Assessment
- Synthesis and Reactivity of Heterocycles
- Bacteriophages and microbial interactions
- Quinazolinone synthesis and applications
- Multicomponent Synthesis of Heterocycles
University of Science and Technology of China
2023
Chinese Academy of Sciences
2023
Central Hospital of Zibo
2017
Affiliated Hospital of Hangzhou Normal University
2016
Bristol-Myers Squibb (United States)
2003-2015
Bristol-Myers Squibb (Germany)
2011-2013
La Jolla Institute For Molecular Medicine
2009
Indiana University Health
2009
Indiana University – Purdue University Indianapolis
2009
DuPont (United States)
1993-1997
Abstract The NS5A replication complex inhibitor, BMS-790052, inhibits hepatitis C virus (HCV) with picomolar potency in preclinical assays. This translated vivo to a substantial antiviral effect single-ascending dose study and 14-day multiple-ascending (MAD) monotherapy study. However, HCV RNA remained detectable genotype 1a–infected patients at the end of MAD In contrast, viral breakthrough was observed less often infected 1b, and, several patients, declined below level quantitation (<25...
ABSTRACT Daclatasvir (DCV; BMS-790052) is a hepatitis C virus (HCV) NS5A replication complex inhibitor (RCI) with picomolar to low nanomolar potency and broad genotypic coverage in vitro . Viral RNA declines have been observed the clinic for both alpha interferon-ribavirin (IFN-α–RBV) IFN-RBV-free regimens that include DCV. Follow-up specimens (up 6 months) from selected subjects treated DCV 14-day monotherapy studies were analyzed genotype phenotype. Variants detected by clonal sequencing...
The iminothiazolidinone BMS-858 (2) was identified as a specific inhibitor of HCV replication in genotype 1b replicon assay via high-throughput screening campaign. A more potent analogue, BMS-824 (18), used resistance mapping studies, which revealed that inhibitory activity related to disrupting the function nonstructural protein 5A. Despite development coherent and interpretable SAR, it subsequently discovered DMSO 18 underwent an oxidation structural rearrangement afford thiohydantoin 47,...
Lead inhibitors that target the function of hepatitis C virus (HCV) nonstructural 5A (NS5A) protein have been identified by phenotypic screening campaigns using HCV subgenomic replicons. The demonstration antiviral activity in HCV-infected subjects NS5A replication complex inhibitor (RCI) daclatasvir (1) spawned considerable interest this mechanistic approach. In Perspective, we summarize medicinal chemistry studies led to discovery 1 and other chemotypes for which resistance maps provide...
ABSTRACT A comparison of the daclatasvir (DCV [BMS-790052]) resistance barrier on authentic or hybrid replicons containing NS5A from hepatitis C virus (HCV) genotypes 1 to 6 (GT-1 -6) was completed using a replicon elimination assay. The data indicated that genotype 1b (GT-1b) has highest relative and 2a (GT-2a M31) lowest. rank order barriers DCV > 4a ≥ 5a 6a ≅ 1a JFH 3a M31. Importantly, in combination with protease inhibitor (PI) eliminated GT-2a M31 RNA at clinically relevant...
MicroRNAs (miRNAs) play important roles in diverse biological processes and are emerging as key regulators of tumorigenesis tumor progression. Among the differentially expressed miRNAs breast cancer, miR-125b was revealed to be deregulated associated with poor prognosis chemoresistance triple-negative cancer (TNBC), but mechanism is still unknown. In our study, we showed downregulated expression TNBC tissues decreased migration invasion miR-125b-expressing Hs578T cells. MAP2K7 then detected...
Various DNA- and RNA-dependent RNA polymerases have been reported to use oligoribonucleotide primers initiate nucleic acid synthesis. For the brome mosaic virus polymerase (RdRp), we determined that in reactions performed with limited GTP concentrations, minus-strand synthesis can be stimulated by inclusion of guanosine monophosphate or specific oligoribonucleotides. Furthermore, guanylyl-3',5'-guanosine (GpG) was incorporated into increased rate In presence GpG, RdRp's Km for decreased from...
Hepatitis C virus (HCV) non-structural protein 5A (NS5A) is a multi-functional that expressed in basally phosphorylated (p56) and hyperphosphorylated (p58) forms. NS5A phosphorylation has been implicated regulating multiple aspects of HCV replication. We recently reported the identification class compounds potently inhibit RNA replication by targeting NS5A. Although precise mechanism inhibition these not well understood, one activity described their ability to block expression form Here, we...
ABSTRACT The exceptional in vitro potency of the hepatitis C virus (HCV) NS5A inhibitor BMS-790052 has translated into an vivo effect proof-of-concept clinical trials. Although 50% effective concentration (EC 50 ) initial lead, thiazolidinone BMS-824, was ∼10 nM replicon assay, it underwent transformation to other inhibitory species after incubation cell culture medium. biological profile including EC , drug required reduce growth by (CC ), and resistance profile, however, remained...
ABSTRACT BMS-790052, a first-in-class hepatitis C virus (HCV) replication complex inhibitor, targeting nonstructural protein 5A (NS5A), displays picomolar to nanomolar potency against genotypes 1 5. This exceptional translated into robust anti-HCV activity in clinical studies with HCV genotype 1-infected subjects. To date, all BMS-790052-associated resistance mutations have mapped the N-terminal region of NS5A. further characterize antiviral replicon elimination and colony formation assays...
The influence of naturally occurring polymorphisms on the potency HCV nonstructural protein 5A (NS5A) replication complex inhibitor, BMS-790052, was investigated by evaluating hybrid replicons in which entire NS5A coding region genotype (GT) la and 1b laboratory (lab) strains (H77c Con1) were replaced with corresponding regions specimens collected from 10 GT-1a- 6 GT-1b-infected subjects. For baseline (BL) specimens, no previously observed resistance variants identified population...
ABSTRACT The hepatitis C virus (HCV) replicon is a unique system for the development of high-throughput screen (HTS), since analysis inhibitors requires quantification decrease in steady-state level HCV RNA. replication dependent on host cell factors, and any toxic effects may have significant impact replication. Therefore, determining antiviral specificity compounds presents challenge identification specific inhibitors. Here we report an HCV/bovine viral diarrhea (BVDV) dual assay suitable...
Mammalian histone mRNAs end in a highly conserved stem-loop structure, with six-base stem and four-base loop. We have examined the effect of mutating on expression mRNA vivo by introducing mutated genes into CHO cells stable transfection. Point mutations been introduced loop sequence UA base pair at top stem. Changing either first or third UYUN to purine greatly reduced expression, while changing both U's purines abolished expression. A number alterations sequence, including reversing two...
The antiviral profile of BMS-790052, a potent hepatitis C virus (HCV) replication complex inhibitor targeting nonstructural protein NS5A, is well characterized for HCV genotype-1. Here, we report that BMS-790052 inhibits hybrid replicons containing genotype-4 NS5A genes with 50% effective concentrations (EC(50)s) ranging from 7 to 13 pM. residue 30 was an important site BMS-790052-selected resistance in the replicons. Our results support potential as valuable component combination therapy...
A series of symmetrical E-stilbene prolinamides that originated from the library-synthesized lead 3 was studied with respect to HCV genotype 1a (G-1a) and 1b (G-1b) replicon inhibition selectivity against BVDV cytotoxicity. SAR emerging an examination prolinamide cap region revealed 11 be a selective NS5A inhibitor exhibiting submicromolar potency both G-1a G-1b replicons. Additional structural refinements resulted in identification 30 as potent, dual G-1a/1b inhibitor.
Compound-1453 was identified and characterized as a specific inhibitor of bovine viral diarrhea virus (BVDV). The concentration compound-1453 which results in 50% protection from virus-induced cytopathic effect is approximately 2.2 microM, with therapeutic index 60, it not active against panel RNA DNA viruses. A time-of-addition experiment suggested that targets stage the life cycle after entry. To determine target compound-1453, resistant generated. Resistant variants grew efficiently...