A5065496874- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Hepatitis C virus research
- HIV Research and Treatment
- Cytomegalovirus and herpesvirus research
- Herpesvirus Infections and Treatments
- Mosquito-borne diseases and control
- Viral Infections and Immunology Research
- Viral-associated cancers and disorders
- Hepatitis B Virus Studies
- RNA and protein synthesis mechanisms
- SARS-CoV-2 and COVID-19 Research
- RNA modifications and cancer
- Monoclonal and Polyclonal Antibodies Research
- Advanced biosensing and bioanalysis techniques
- Immunodeficiency and Autoimmune Disorders
- Chronic Lymphocytic Leukemia Research
- Viral gastroenteritis research and epidemiology
- Toxin Mechanisms and Immunotoxins
- Virus-based gene therapy research
- HIV/AIDS Research and Interventions
- Malaria Research and Control
- Synthesis and Biological Evaluation
- Viral Infections and Vectors
- Calcium signaling and nucleotide metabolism
Atea Pharmaceuticals (United States)
2017-2025
University of Helsinki
2023
Merck (Germany)
2015
Idera Pharmaceuticals (United States)
2009-2015
Tel Aviv University
2009
AstraZeneca (United States)
2008
Research Triangle Park Foundation
1981-2002
GlaxoSmithKline (United States)
2002
Burroughs Wellcome Fund
1990
Triangle
1990
The gene encoding cytosine deaminase (CD) has been expressed in the human colorectal carcinoma cell line WiDr. Metabolism studies confirm that tumor cells expressing CD convert very nontoxic prodrug 5-fluorocytosine (5FCyt) to 5-fluorouracil (5FUra) and 5FUra metabolites. Tumor xenografts composed of CD-expressing can selectively generate levels > 400 microM when host mouse is dosed with 5FCyt. selective metabolic conversion 5FCyt results inhibition thymidylate synthase incorporation into...
1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, is a carbocyclic nucleoside with unique biological profile giving potent, selective anti-human immunodeficiency virus (HIV) activity. 1592U89 was selected after evaluation of wide variety analogs containing cyclopentene substitution for the 2'-deoxyriboside natural deoxynucleosides, optimizing in vitro anti-HIV potency, oral bioavailability, and central nervous system (CNS) penetration. equivalent...
The impact of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent COVID-19, is global and unprecedented. Although remdesivir has recently been approved by FDA to treat SARS-CoV-2 infection, no oral antiviral available for outpatient treatment.
Abstract The guanosine analog AT-527 represents a promising candidate against Severe Acute Respiratory Syndrome coronavirus type 2 (SARS-CoV-2). recently entered phase III clinical trials for the treatment of COVID-19. Once in cells, is converted into its triphosphate form, AT-9010, that presumably targets viral RNA-dependent RNA polymerase (RdRp, nsp12), incorporation RNA. Here we report 2.98 Å cryo-EM structure SARS-CoV-2 nsp12-nsp7-nsp8 -RNA complex, showing AT-9010 bound at three sites...
Benzimidazole nucleosides have been shown to be potent inhibitors of human cytomegalovirus (HCMV) replication in vitro. As part the exploration structure-activity relationships within this series, we synthesized 2-isopropylamino derivative (3322W93) 1H-beta-D-ribofuranoside-2-bromo-5,6-dichlorobenzimidazole (BDCRB) and biologically unnatural L-sugars corresponding both compounds. One L derivatives, 1H-beta-L-ribofuranoside-2-isopropylamino-5,6-dichlorobenzimidazole (1263W94), showed...
The anabolism of 1592U89, (-)-(1S,4R)-4-[2-amino-6-(cyclopropylamino)-9H-purin-9-yl]-2-cyclo pentene-1-methanol, a selective inhibitor human immunodeficiency virus (HIV), was characterized in T-lymphoblastoid CD4+ CEM cells. 1592U89 ultimately anabolized to the triphosphate (TP) guanine analog (-)-carbovir (CBV), potent HIV reverse transcriptase. However, less than 2% intracellular converted CBV, an amount insufficient account for CBV-TP levels observed. its 5'-monophosphate (MP) by recently...
The disposition and safety of the antiviral drug acyclovir were studied in 14 subjects with advanced malignancies. Acyclovir was administered by a 1‐hr intravenous infusion at doses 0.5, 1.0, 2.5, 5.0 mg/kg. At end infusion, mean peak plasma levels (±SEM), determined radioimmunoassay, 6.4 ±0.7, 12.1 ±2.3, 14.9 ±2.7, 33.7 ±7.1 µM. concentration‐time profiles could be described biexponential equation. half‐life slow phase ranged from 2.2 to 5 hr detected for least 18 after infusion. total body...
The anti-human immunodeficiency virus drug zidovudine is metabolized extensively in human beings to the 5'-glucuronide (GAZT) and cleared rapidly, resulting a short half-life need for frequent dosing. This study explores whether probenecid, which also by glucuronidation, reduces clearance when administered orally patients with acquired syndrome (AIDS) or AIDS-related complex (ARC). mean plasma levels were significantly higher after concurrent administration of probenecid than its absence,...
ABSTRACT 1263W94 is a novel benzimidazole compound being developed for treatment of human cytomegalovirus infection. No adverse pharmacological effects were demonstrated in safety pharmacology studies with 1263W94. The minimal-effect dose 1-month rat study was 100 mg/kg/day, and the no-effect monkey 180 mg/kg/day. Toxic limited to increases liver weights, neutrophils, monocytes at higher doses female rats. not genotoxic Ames or micronucleus assays. In mouse lymphoma assay, mutagenic absence...
The kinetic and metabolic disposition of (8-14C)acyclovir (ACV) was investigated in five subjects with advanced malignancy. drug administered by 1-hr intravenous infusion at doses 0.5 2.5 mg/kg. Plasma blood radioactivity-time, plasma concentration-time data were defined a two-compartment open model. There nearly equivalent distribution radioactivity plasma. overall mean half-life total body clearance +/- SD ACV 2.1 hr 297 53 ml/min/1.73 m2. Binding to proteins 15.4 4.4%. Most the...
Despite the availability of highly effective direct-acting antiviral (DAA) regimens for treatment hepatitis C virus (HCV) infections, sustained viral response (SVR) rates remain suboptimal difficult-to-treat patient populations such as those with HCV genotype 3, cirrhosis or prior experience, warranting development more potent replication antivirals. AT-527 is hemi-sulfate salt AT-511, a novel phosphoramidate prodrug 2'-fluoro-2'-C-methylguanosine-5'-monophosphate that has in vitro activity...
Every year, millions of people worldwide are infected with dengue virus (DENV), a significant number developing severe life-threatening disease. There currently no broadly indicated vaccines or therapeutics available for treatment DENV infection. Here, we show that AT-281, the free base AT-752, an orally double prodrug guanosine nucleotide analog, was potent inhibitor serotypes 2 and 3 in vitro, requiring concentrations 0.48 0.77 μM, respectively, to inhibit viral replication by 50% (EC50)...
A major metabolite of zidovudine (3'-azido-3'-deoxythymidine, AZT), which previously had not been observed in a variety experimental animals, was identified samples plasma and urine from cynomolgus monkeys patient treated with AZT. The urinary recoveries the were, respectively, 1.5- 6.9-fold higher than unchanged drug. purified gram quantities urines enzymatically, using beta-glucuronidase specific inhibitor enzyme, as glucuronide conjugate formed vitro by incubating AZT preparations human...
AT-527 is a novel modified guanosine nucleotide prodrug inhibitor of the hepatitis C virus (HCV) NS5B polymerase, with increased in vitro antiviral activity as compared to sofosbuvir and highly differentiated favorable preclinical profile other anti-HCV nucleoside/nucleotide analogs. This was multiple part clinical study where ascending doses up 600 mg (expressed salt form; equivalent 553 free base) once daily for seven days were evaluated randomized, double-blind, placebo-controlled...
Bemnifosbuvir (BEM), the orally available hemisulfate salt of double prodrug a guanosine nucleotide analog, is potent, selective, and pan-genotypic inhibitor HCV nonstructural protein 5B, an RNA-dependent RNA polymerase necessary for viral replication. Similarly, ruzasvir (RZR) available, highly 5A, essential component replication complex. The antiviral effects combination these two complementary direct-acting antivirals were determined in GT1b Huh-7 replicon cells. Two independent vitro...
Bemnifosbuvir (AT-527) and AT-752 are guanosine analogues currently in clinical trials against several RNA viruses. Here, we show that these drugs require a minimal set of 5 cellular enzymes for activation to their common 5′-triphosphate AT-9010, with an obligate order reactions. AT-9010 selectively inhibits essential viral enzymes, accounting antiviral potency. Functional structural data at atomic resolution decipher N 6 -purine deamination compatible its metabolic activation. Crystal...
The acyclic nucleoside analogue, acyclovir, is an antiviral drug with activity against the herpes group of DNA viruses. Clinically, it used as a selective therapeutic agent for treatment simplex and varicella-zoster virus infections. Studies on disposition during course its preclinical clinical development, indicated significant species differences in absorption, metabolism elimination drug. Gastrointestinal absorption was adequate dogs mice; but rats primates limited to less than 20%...
The tissue distribution and metabolic fate of [5'-3H]zidovudine was studied in rats after a single dose 10 mg/kg by gavage. drug absorbed rapidly distributed into all tissues. Peak blood levels were observed 0.25 hr post-dose. level peak radioactivity the stomach, intestine, liver, spleen, adrenals, kidney higher than plasma, while heart, lung, thymus, lymph nodes, muscle, bone, skin it similar to that plasma. Only testes brain lower Blood plasma nearly equivalent. A biphasic disappearance...
Yellow fever virus (YFV) is a zoonotic pathogen re-emerging in parts of the world, causing viral hemorrhagic associated with high mortality rates. While an effective vaccine available, having antiviral against YFV critical unexpected outbreaks, or when vaccination not recommended. We have previously identified AT-281, free base AT-752, orally available double prodrug guanosine nucleotide analog, as potent inhibitor vitro, 50% concentration (EC50) 0.31 μM. In hamsters infected (Jimenez...