A5067721967- Hepatitis B Virus Studies
- Hepatitis C virus research
- HIV/AIDS drug development and treatment
- Blood Coagulation and Thrombosis Mechanisms
- HIV Research and Treatment
- Liver Disease Diagnosis and Treatment
- RNA and protein synthesis mechanisms
- Hemophilia Treatment and Research
- Platelet Disorders and Treatments
- Coagulation, Bradykinin, Polyphosphates, and Angioedema
- Hepatitis Viruses Studies and Epidemiology
- Protein Kinase Regulation and GTPase Signaling
- DNA and Nucleic Acid Chemistry
- Bacterial Genetics and Biotechnology
- Fungal and yeast genetics research
- RNA modifications and cancer
- Monoclonal and Polyclonal Antibodies Research
- Biochemical and Molecular Research
- Immune Cell Function and Interaction
- Computational Drug Discovery Methods
- Advanced biosensing and bioanalysis techniques
- Blood properties and coagulation
- Pneumocystis jirovecii pneumonia detection and treatment
- Protease and Inhibitor Mechanisms
- Bacterial Infections and Vaccines
Gilead Sciences (United States)
2000-2012
University of Cambridge
2004
May Institute
2004
University of Chicago
2004
Gilead Sciences (Germany)
2004
Victorian Infectious Diseases Reference Laboratory
2002
University of Southern California
2002
Gilead Sciences (Australia)
2002
Rutgers, The State University of New Jersey
2001
Vanderbilt University
1998
A systematic mutagenesis strategy was used to identify the functional regions and residues of a protein kinase.Clusters charged amino acids in catalytic subunit Saccharomyces cerevisiae CAMPdependent kinase, were systematically mutated alanine, producing set mutations that encompassed entire molecule.Residues indispensable for enzyme activity identified by testing ability mutants function vivo.Active assayed vitro, with reduced specific subsequently analyzed steady-state kinetics determine...
ABSTRACT Success in treating hepatitis B virus (HBV) infection with nucleoside analog drugs like lamivudine is limited by the emergence of drug-resistant viral strains upon prolonged therapy. The predominant resistance mutations HBV-infected patients are Met552IIe and Met552Val (Met552Ile/Val), frequently association a second mutation, Leu528Met. effects Leu528Met, Met552Ile, on binding HBV polymerase inhibitors natural substrate dCTP were evaluated using an vitro assay. Susceptibility to...
ABSTRACT Therapy of chronic hepatitis B virus (HBV) infection with the polymerase inhibitor lamivudine frequently is associated emergence viral resistance. Genotypic changes in YMDD motif (reverse transcriptase [rt] mutations rtM204V/I) conferred resistance to as well reducing vitro replication efficiency HBV. A second mutation, rtL180M, was previously reported partially restore fitness augment drug vitro. Here we report functional characterization a third mutation (rtV173L) and famciclovir....
To determine whether adefovir is active against lamivudine-resistant hepatitis B virus (HBV), the inhibition constants of diphosphate and lamivudine triphosphate for wild-type mutant human HBV DNA polymerases, which contain amino acid substitutions associated with resistance, were compared. Recombinant polymerases expressed substantially purified using a baculovirus expression system immunoaffinity chromatography. polymerase mutants M552I, M552V, L528M/M552V showed resistance to (Ki)...
In a recent phase II clinical study, 13 chronic hepatitis B-infected patients treated daily with 30 mg adefovir dipivoxil for 12 weeks displayed median 4.1-log10 decrease in plasma B virus (HBV)-DNA levels. The decline of viral load during therapy biphasic kinetic profile that was modeled to determine the efficacy inhibition production, as well constants clearance free and loss infected cells. Viral production suppressed an 0.993 +/- 0.008, indicating only 0.7% persisted therapy. initial,...
ABSTRACT GS-7340 and GS-9131 {9-[( R )-2-[[( S )-[[( )-1-(isopropoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]-propyl]adenine 9-( )-4′-( )-[[[( )-1-[(ethoxycarbonyl)ethyl]amino]phenoxyphosphinyl]methoxy]-2′-fluoro-1′-furanyladenine, respectively} are novel alkylalaninyl phenyl ester prodrugs of tenofovir {9- -[(2-phosphonomethoxy)propyl]adenine} (TFV) a cyclic nucleotide analog, GS-9148 (phosphonomethoxy-2′-fluoro-2′, 3′-dideoxydidehydroadenosine), respectively. Both exhibit potent...
CD8 + T cells are key antiviral effectors against hepatitis B virus (HBV), yet their number and function can be compromised in chronic infections. Preclinical HBV models displaying cell dysfunction showed that interleukin-2 (IL-2)–based treatment, unlike programmed death ligand 1 (PD-L1) checkpoint blockade, could reverse this defect, suggesting its therapeutic potential HBV. However, IL-2’s effectiveness is hindered by pleiotropic nature, because receptor found on various immune cells,...
In vitro studies have shown that lamivudine and penciclovir (the active metabolite of famciclovir) act synergistically to inhibit hepatitis B virus (HBV) replication. We compared the effectiveness HBV viral suppression by monotherapy versus plus famciclovir combination therapy in Chinese patients with chronic infection. Twenty-one e antigen (HBeAg)-positive patients, detectable DNA (Digene Hybrid Capture II), were randomized receive either 150 mg/d orally (group 1, 9 patients) or 500 mg 3...
Current therapies for chronic hepatitis B virus (HBV) infection do not provide adequate long-term control of viral replication in the majority patients. Monotherapy with nucleoside analogs, such as lamivudine and famciclovir, is effective short periods but results emergence drug-resistant HBV a substantial number patients within 1 year therapy. Adefovir dipivoxil (ADV) has demonstrated clinical activity against wild-type lamivudine-resistant HBV, it unclear whether resistance mutations will...
Utilizing site-directed mutagenesis, 77 charged and polar residues that are highly exposed on the surface of human thrombin were systematically substituted with alanine. Functional assays using mutants identified required for recognition cleavage procoagulant substrate fibrinogen (Lys21, Trp50, Lys52, Asn53+Thr55, Lys65, His66, Arg68, Tyr71, Arg73, Lys77, Lys106+Lys107, Asp193+Lys196, Glu202, Glu229, Arg233, Asp234) anticoagulant protein C Arg233), interactions cofactor thrombomodulin...
Seven hundred nucleoside treatment–naive patients were enrolled in two phase 3 trials of adefovir dipivoxil (ADV) for the treatment chronic hepatitis B. To monitor emergence potential resistance mutations over first 48 weeks, all intent–to–treat (467 ADV–treated and 228 placebo patients) included a prospectively defined, treatment–blinded, virology substudy. The study protocol mandated genotypic analysis with detectable B virus (HBV) DNA by Roche Amplicor polymerase chain reaction (PCR) at...
A library of mutants the catalytic subunit Saccharomyces cerevisiae cAMP-dependent protein kinase was screened in vitro for defective recognition regulatory subunit. The mutations identified were mapped onto three-dimensional structure mouse with a peptide inhibitor. Mutations both and substrate Leu-Arg-Arg-Ala-Ser-Leu-Gly (Kemptide) to peptide-binding site shared by all substrates inhibitors functionally define binding autoinhibitor sequence hinge region Mutants only residues that comprise...
Background. Mutations in the hepatitis B virus (HBV) genome may occur during therapy. Methods. We report an asymptomatic HBV carrier who underwent transplantation for end-stage renal disease. She developed flare 6 months after and was placed on lamivudine. After initial rapid improvement, she relapsed clinically virologically. decompensated with jaundice, peripheral edema, ascites, encephalopathy, coagulopathy, hepatorenal syndrome. A liver biopsy specimen revealed submassive necrosis....
Edema factor (EF), a key virulence in anthrax pathogenesis, has calmodulin (CaM)-activated adenylyl cyclase activity. We have found that adefovir dipivoxil, drug approved to treat chronic infection of hepatitis B virus, effectively inhibits EF-induced cAMP accumulation and changes cytokine production mouse primary macrophages. Adefovir diphosphate (PMEApp), the active cellular metabolite activity EF vitro with high affinity ( K i = 27 nM). A crystal structure EF-CaM-PMEApp reveals catalytic...
ABSTRACT The elimination of viral covalently closed circular DNA (CCC DNA) from the nucleus infected hepatocytes is an obstacle to achieving sustained clearance during antiviral therapy chronic hepatitis B virus (HBV) infection. aim our study was determine whether treatment with adefovir, a new acyclic nucleoside phosphonate, prodrug which, adefovir dipivoxil, in clinical evaluation, able suppress CCC both vitro and vivo using duck HBV (DHBV) model. First, effect on synthesis examined...
Combination therapies may be required for long-term management of some patients chronically infected with hepatitis B virus (HBV). Adefovir is a nucleotide analog that has similar activity against wild-type and lamivudine-resistant HBV. In contrast to lamivudine, clinical resistance the prodrug adefovir dipivoxil emerges infrequently. Based on its efficacy low frequency resistance, form an important component combination regimens. We therefore investigated in vitro antiviral combinations...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTIdentification of electrostatic interactions that determine the phosphorylation site specificity cAMP-dependent protein kinaseCraig S. Gibbs and Mark J. ZollerCite this: Biochemistry 1991, 30, 22, 5329–5334Publication Date (Print):June 1, 1991Publication History Published online1 May 2002Published inissue 1 June 1991https://doi.org/10.1021/bi00236a001RIGHTS & PERMISSIONSArticle Views141Altmetric-Citations57LEARN ABOUT THESE METRICSArticle Views are...