A5031221529- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Biochemical and Molecular Research
- Hepatitis C virus research
- Hepatitis B Virus Studies
- Drug Transport and Resistance Mechanisms
- Cytomegalovirus and herpesvirus research
- Liver Disease Diagnosis and Treatment
- Cell Adhesion Molecules Research
- Pharmacological Effects and Toxicity Studies
- Chronic Lymphocytic Leukemia Research
- HIV/AIDS Research and Interventions
- Pulmonary Hypertension Research and Treatments
- Pneumocystis jirovecii pneumonia detection and treatment
- Monoclonal and Polyclonal Antibodies Research
- HIV-related health complications and treatments
- Viral Infections and Outbreaks Research
- Immunotherapy and Immune Responses
- Metabolism and Genetic Disorders
- SARS-CoV-2 and COVID-19 Research
- Crystallization and Solubility Studies
- Viral gastroenteritis research and epidemiology
- Folate and B Vitamins Research
- X-ray Diffraction in Crystallography
- Cancer Immunotherapy and Biomarkers
Gilead Sciences (United States)
2011-2023
Harmonic Drive (Germany)
2023
Adrian College
2021
University of Washington
2016-2017
Bristol-Myers Squibb (United States)
2016-2017
Merck & Co., Inc., Rahway, NJ, USA (United States)
2016-2017
Biogen (United States)
2016-2017
Takeda (United States)
2016-2017
University of Kansas Medical Center
2016
University of California, San Francisco
2016
Broad-spectrum antiviral GS-5734 inhibits both epidemic and zoonotic coronaviruses in vitro vivo.
Emerging coronaviruses (CoVs) cause severe disease in humans, but no approved therapeutics are available. The CoV nsp14 exoribonuclease (ExoN) has complicated development of antiviral nucleosides due to its proofreading activity. We recently reported that the nucleoside analogue GS-5734 (remdesivir) potently inhibits human and zoonotic CoVs vitro a acute respiratory syndrome coronavirus (SARS-CoV) mouse model. However, studies with have not resistance associated GS-5734, nor do we understand...
The recent Ebola virus (EBOV) outbreak in West Africa was the largest recorded history with over 28,000 cases, resulting >11,000 deaths including >500 healthcare workers. A focused screening and lead optimization effort identified 4b (GS-5734) anti-EBOV EC50 = 86 nM macrophages as clinical candidate. Structure activity relationships established that 1'-CN group C-linked nucleobase were critical for optimal potency selectivity against host polymerases. robust diastereoselective synthesis...
Abstract GS-5734 is a monophosphate prodrug of an adenosine nucleoside analog that showed therapeutic efficacy in non-human primate model Ebola virus infection. It has been administered under compassionate use to two patients, both whom survived, and currently Phase 2 clinical development for treatment disease. Here we report the antiviral activities parent across multiple families, providing evidence support new indications this compound against human viruses significant public health concern.
To examine the role of mitochondrial polymerase (Pol γ) in clinically observed toxicity nucleoside analogs used to treat AIDS, we examined kinetics incorporation catalyzed by Pol γ for each Food and Drug Administration-approved analog plus 1-(2-deoxy-2-fluoro-β-d-arabinofuranosyl)-5-iodouracil (FIAU), β-L-(−)-2′,3′-dideoxy-3′-thiacytidine (−)3TC, (<i>R</i>)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). We recombinant exonuclease-deficient (E200A), reconstituted human holoenzyme single...
Nucleotide analog inhibitors have shown clinical success in the treatment of hepatitis C virus (HCV) infection, despite an incomplete mechanistic understanding NS5B, viral RNA-dependent RNA polymerase. Here we study details HCV replication by determining crystal structures stalled polymerase ternary complexes with enzymes, templates, primers, incoming nucleotides, and catalytic metal ions during both primed initiation elongation synthesis. Our analysis revealed that highly conserved...
ABSTRACT Tenofovir (TFV) undergoes renal elimination by a combination of glomerular filtration and active tubular secretion. While transporter-mediated uptake TFV from the blood into proximal-tubule cells has been well characterized, comparatively little is known about efflux system responsible for transporting lumen during Therefore, members ATP-binding cassette family pumps expressed at apical side were studied ability to transport TFV. Studies in multiple independent vitro systems show...
Many xenobiotics including the pharmacoenhancer cobicistat increase serum creatinine by inhibiting its renal active tubular secretion without affecting glomerular filtration rate. This study aimed to define transporters involved in secretion, applying that knowledge establish mechanism for xenobiotic-induced effects. The basolateral uptake organic anion transporter OAT2 and cation OCT2 OCT3 were found transport creatinine. At physiologic concentrations, specific activity of was over twofold...
Pharmacologic inhibition of acetyl‐CoA carboxylase (ACC) enzymes, ACC1 and ACC2, offers an attractive therapeutic strategy for nonalcoholic fatty liver disease (NAFLD) through simultaneous acid synthesis stimulation oxidation. However, the effects ACC on hepatic mitochondrial oxidation, anaplerosis, ketogenesis in vivo are unknown. Here, we evaluated effect a liver‐directed allosteric inhibitor ACC2 (Compound 1) these parameters, as well glucose lipid metabolism, control diet‐induced rodent...
Tenofovir is an acyclic nucleotide analog with activity against human immunodeficiency virus (HIV) and hepatitis B (HBV). disoproxil fumarate (tenofovir DF), a bis-alkoxyester prodrug of tenofovir, approved for the treatment HIV currently being developed to treat chronic B. In this report, we further characterize in vitro tenofovir HBV as well its metabolism hepatic cells. We show that efficiently phosphorylated diphosphate (TFV-DP) both HepG2 cells primary hepatocytes. TFV-DP has long...
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...
Ribonucleoside analogues have potential utility as anti-viral, -parasitic, -bacterial and -cancer agents. However, their clinical applications been limited by off target effects. Development of antiviral ribonucleosides for treatment hepatitis C virus (HCV) infection has hampered appearance toxicity during trials that evaded detection preclinical studies. It is well established the human mitochondrial DNA polymerase an deoxyribonucleoside reverse transcriptase inhibitors. Here we test...
The experimental pharmacoenhancer cobicistat (COBI), a potent mechanism-based inhibitor of cytochrome P450 3A enzymes, was found to inhibit the intestinal efflux transporters P-glycoprotein and breast cancer resistance protein. Consistent with its transporter inhibition, COBI significantly increased absorptive flux potential candidates for clinical coadministration, including HIV protease inhibitors atazanavir darunavir lymphoid cell- tissue-targeted prodrug nucleotide analog tenofovir,...
Hepatitis C virus (HCV) infection presents an unmet medical need requiring more effective treatment options. Nucleoside inhibitors (NI) of HCV polymerase (NS5B) have demonstrated pan-genotypic activity and durable antiviral response in the clinic, they are likely to become a key component future regimens. NI candidates that entered clinical development thus far all been N-nucleoside derivatives. Herein, we report discovery C-nucleoside class NS5B inhibitors. Exploration adenosine analogs...
Although data are available on the change of expression/activity drug-metabolizing enzymes in liver cirrhosis patients, corresponding transporter protein expression not available. Therefore, using quantitative targeted proteomics, we compared our previous noncirrhotic control livers (n = 36) with major hepatobiliary transporters, breast cancer resistance (BCRP), bile salt export pump (BSEP), multidrug and toxin extrusion 1 (MATE1), resistance-associated (MRP)2, MRP3, MRP4, sodium...
GS-7340 is a prodrug of tenofovir (TFV) that more efficiently delivers TFV into lymphoid cells and tissues than the clinically used disoproxil fumarate, resulting in higher antiviral potency at greatly reduced doses lower systemic exposure. First-pass extraction by intestine liver represents substantial barriers to oral delivery prodrugs designed for rapid intracellular hydrolysis. In order understand how reduces first-pass clearance be an effective prodrug, its permeability stability were...
The biguanide metformin is widely used as first-line therapy for the treatment of type 2 diabetes. Predominately a cation at physiological pH's, transported by membrane transporters, which play major roles in its absorption and disposition. Recently, our laboratory demonstrated that organic transporter 1, OCT1, hepatic uptake metformin, was also primary thiamine, vitamin B1. In this study, we tested reverse, i.e., substrate thiamine transporters (THTR-1, SLC19A2, THTR-2, SLC19A3). Our study...