A5102861651- HIV/AIDS drug development and treatment
- Hepatitis C virus research
- HIV Research and Treatment
- Biochemical and Molecular Research
- SARS-CoV-2 and COVID-19 Research
- Respiratory viral infections research
- COVID-19 Clinical Research Studies
- Cytomegalovirus and herpesvirus research
- DNA Repair Mechanisms
- Hepatitis B Virus Studies
- Viral gastroenteritis research and epidemiology
- Adipose Tissue and Metabolism
- Adenosine and Purinergic Signaling
- Viral Infections and Immunology Research
- Renal Transplantation Outcomes and Treatments
- Virus-based gene therapy research
- Metalloenzymes and iron-sulfur proteins
- Animal Virus Infections Studies
- Metal-Catalyzed Oxygenation Mechanisms
- SARS-CoV-2 detection and testing
- Liver Disease Diagnosis and Treatment
- Immunodeficiency and Autoimmune Disorders
- Hormonal Regulation and Hypertension
- Microbial metabolism and enzyme function
- Mycobacterium research and diagnosis
Gilead Sciences (United States)
2014-2024
Hiroshima City Asa Citizens Hospital
2016
Princeton University
2010-2013
Yale University
2003-2012
Kaohsiung Medical University
2007
Emory University
2003
University of Georgia
1998-2003
University of Nebraska–Lincoln
1998-2001
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of novel viral disease COVID-19. With no approved therapies, this pandemic illustrates urgent need for broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV) potently inhibits replication in human lung cells primary airway epithelial cultures (EC50 = 0.01 μM). Weaker activity observed Vero E6 1.65 μM) because their low capacity to metabolize RDV....
The aim of this study was to determine the safety and efficacy nucleoside analog GS-441524 for cats suffering from various forms naturally acquired feline infectious peritonitis (FIP).
Feline infectious peritonitis (FIP) is a common and highly lethal coronavirus disease of domestic cats. Recent studies diseases caused by several RNA viruses in people other species indicate that antiviral therapy may be effective against FIP The small molecule nucleoside analog GS-441524 molecular precursor to pharmacologically active triphosphate molecule. These analogs act as an alternative substrate RNA-chain terminator viral dependent polymerase. We determined was non-toxic feline cells...
The coronavirus disease 2019 (COVID-19) pandemic remains uncontrolled despite the rapid rollout of safe and effective severe acute respiratory syndrome 2 (SARS-CoV-2) vaccines, underscoring need to develop highly antivirals. In setting waning immunity from infection vaccination, breakthrough infections are becoming increasingly common treatment options remain limited. addition, emergence SARS-CoV-2 variants concern, with their potential escape neutralization by therapeutic monoclonal...
ABSTRACT Tenofovir alafenamide (TAF) is a prodrug of tenofovir (TFV) currently in clinical evaluation for treatment HIV and hepatitis B virus (HBV) infections. Since the target tissue HBV liver, hepatic delivery metabolism TAF primary human hepatocytes vitro dogs vivo were evaluated here. Incubation with resulted high levels pharmacologically active metabolite diphosphate (TFV-DP), which persisted cell half-life >24 h. In addition to passive permeability, studies transfected lines suggest...
A discovery program targeting respiratory syncytial virus (RSV) identified
Remdesivir (RDV; GS-5734, Veklury), the first FDA-approved antiviral to treat COVID-19, is a single-diastereomer monophosphoramidate prodrug of an adenosine analogue. RDV taken up in target cells and metabolized multiple steps form active nucleoside triphosphate (TP) (GS-443902), which, turn, acts as potent selective inhibitor viral RNA polymerases.
Remdesivir (RDV, GS-5734), the first FDA-approved antiviral for treatment of COVID-19, is a single diastereomer monophosphoramidate prodrug an adenosine analogue. It intracellularly metabolized into active triphosphate form, which in turn acts as potent and selective inhibitor multiple viral RNA polymerases. RDV has broad-spectrum activity against members coronavirus family, such SARS-CoV-2, SARS-CoV, MERS-CoV, well filoviruses paramyxoviruses. To assess potential off-target toxicity, was...
Remdesivir (RDV) is a nucleotide analog prodrug with demonstrated clinical benefit in patients coronavirus disease 2019 (COVID-19). In October 2020, the US FDA approved intravenous (IV) RDV as first treatment for hospitalized COVID-19 patients. Furthermore, has been or authorized emergency use more than 50 countries. To make convenient non-hospitalized earlier disease, alternative routes of administration are being evaluated. Here, we investigated pharmacokinetics and efficacy administered...
Several hypotheses have been proposed to explain the development of resistance anti-HIV drug AZT. Clinical findings show that AZT mutations in HIV-1 reverse transcriptase (RT) not only reduce susceptibility thymidine analogues but may also confer multi-dideoxynucleoside resistance. In this report, we describe transient kinetic studies establishing biochemical effects RT on incorporation and removal natural unnatural deoxynucleotides. While physiological role remains be elucidated, largest...
The anti-hepatitis C virus nucleotide prodrug GS-6620 employs a double-prodrug approach, with l-alanine-isopropyl ester and phenol moieties attached to the 5'-phosphate that release nucleoside monophosphate in hepatocytes 3'-isobutyryl added improve permeability oral bioavailability. Consistent stability found intestinal homogenates, following administration, intact levels blood plasma were highest dogs, followed by monkeys, then lowest hamsters. In contrast, liver of triphosphate metabolite...
SUMMARY Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of novel pandemic viral disease COVID-19. With no approved therapies, this illustrates urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug an adenosine analog, potently inhibits replication human lung cells primary airway epithelial cultures (EC 50 = 0.01 μM). Weaker...
Emtricitabine [(-)FTC; (-)-beta-L-2'-3'-dideoxy-5-fluoro-3'-thiacytidine] is an oxathiolane nucleoside analog recently approved by the Food and Drug Administration for treatment of human immunodeficiency virus (HIV). Structurally, (-)FTC closely resembles lamivudine [(-)3TC] except that former 5-fluorinated on cytosine ring. In HIV-1 reverse transcriptase (RT) enzymatic assays, triphosphate [(-)FTC-TP] was incorporated into both DNA-DNA DNA-RNA primer-templates nearly 3- 10-fold more...
ABSTRACT All currently approved antiviral drugs for the treatment of chronic hepatitis B virus (HBV) infection are nucleos(t)ide reverse transcriptase inhibitors (NRTI), which inhibit DNA synthesis activity HBV polymerase. The polymerase is a unique (RT) that has novel protein priming in HP initiates viral using itself as primer. We have determined ability NRTI-triphosphates (TP) to and their mechanisms action. While entecavir-TP (a dGTP analog) inhibited initiated specifically with dGTP,...
The heterodisulfide reductase (HDR) from Methanosarcina thermophila was purified to homogeneity acetate-grown cells. In the absence of detergents, HDR consisted an eight-protein complex with hydrogenase activity. However, when in presence 0.6% Triton X-100, a two-subunit (53 and 27 kDa) high specific activity ( approximately 200 units mg-1) enzyme obtained that lacked Sedimentation equilibrium experiments demonstrated has molecular mass 206 kDa partial volume (0.9 cm3/g), indicating protein...
ABSTRACT Sofosbuvir and ribavirin exert their anti-hepatitis C virus (anti-HCV) activity following metabolic activation in the liver. However, intrahepatic concentrations of pharmacologically active nucleotide metabolites humans are poorly characterized due to inaccessibility tissue technical challenges with measuring levels. A clinical study assessing efficacy sofosbuvir administered prior liver transplantation prevent HCV recurrence provided a unique opportunity quantify human We analyzed...
The COVID-19 pandemic remains uncontrolled despite the rapid rollout of safe and effective SARS-CoV-2 vaccines, underscoring need to develop highly antivirals. In setting waning immunity from infection vaccination, breakthrough infections are becoming increasingly common treatment options remain limited. Additionally, emergence variants concern with their potential escape therapeutic monoclonal antibodies emphasizes second-generation oral antivirals targeting conserved viral proteins that...
Human N6-methyl-AMP/dAMP aminohydrolase has been shown to be involved in metabolism of pharmacologically important N6-substituted purine nucleosides and 5′-monophosphate prodrugs thereof. This enzyme was cloned expressed E. coli, mass spectroscopic analysis followed by amino acid sequence analyses indicated that the protein adenosine deaminase-like isoform 1 (ADAL1). An extensive structure–activity relationship study showed ADAL1 able catalyze removal different alkyl groups not only from or...
Induction potentials of the pregnane X receptor (PXR) activator rifampin (RIF) on transporter genes [e.g., organic anion-transporting polypeptides (OATPs)] are still in its infancy or remain controversial field. The present investigations characterized changes gene expression by RIF sandwich-cultured hepatocytes from multiple donors human and cynomolgus monkey using real-time quantitative reverse transcription polymerase chain reaction method. Three-day treatment significantly induced CYP3A4...
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in 2019 as the causative agent of novel pandemic viral disease COVID-19. With no approved therapies, this illustrates urgent need for safe, broad-spectrum antiviral countermeasures against SARS-CoV-2 and future emerging CoVs. We report that remdesivir (RDV), a monophosphoramidate prodrug an adenosine analog, potently inhibits replication human lung cells primary airway epithelial cultures (EC50 = 0.01 µM). Weaker activity...
F 420 H 2 ‐dependent CoB‐S‐S‐CoM reduction as catalyzed by the :heterodisulfide oxidoreductase from Methanosarcina strains was observed in a defined system containing purified dehydrogenase mazei Gö1, 2‐hydroxyphenazine and heterodisulfide reductase thermophila . The process could be divided into two partial reactions: (1) reducing equivalents were transferred to with V max value of 12 U/mg protein; (2) reduced acted electron donor for reductase. specific activity 14–16 protein at 37°C 60–70...
PSI-352938 is a novel cyclic phosphate prodrug of β-D-2'-deoxy-2'-α-fluoro-2'-β-C-methylguanosine-5'-monophosphate with potent anti-HCV activity. In order to inhibit the NS5B RNA-dependent RNA polymerase, must be metabolized active triphosphate form, PSI-352666. During in vitro incubations PSI-352938, significantly larger amounts PSI-352666 were formed primary hepatocytes than clone A hepatitis C virus (HCV) replicon cells. Metabolism and biochemical assays performed define molecular...