A5087545685- HIV/AIDS drug development and treatment
- Biochemical and Molecular Research
- Hepatitis C virus research
- Hepatitis B Virus Studies
- HIV Research and Treatment
- RNA modifications and cancer
- Influenza Virus Research Studies
- Cytomegalovirus and herpesvirus research
- RNA and protein synthesis mechanisms
- RNA Research and Splicing
- Herpesvirus Infections and Treatments
- Cancer, Hypoxia, and Metabolism
- Neonatal Health and Biochemistry
- Click Chemistry and Applications
- Monoclonal and Polyclonal Antibodies Research
- Viral Infections and Immunology Research
- Chemical Synthesis and Analysis
- Liver Disease Diagnosis and Treatment
- interferon and immune responses
- Muscle Physiology and Disorders
- Respiratory viral infections research
- Advanced biosensing and bioanalysis techniques
- Neurogenetic and Muscular Disorders Research
- HIV/AIDS Research and Interventions
- Immune Cell Function and Interaction
PTC Therapeutics (United States)
2013-2023
Tufts University
2016
Eli Lilly (United States)
1990-2002
Charles Humbert 8
2001
Australian National University
1997
University of Oklahoma Health Sciences Center
1997
University of Cincinnati Medical Center
1996
University Hospital and Clinics
1985-1990
Louisiana State University
1985-1990
University Medical Center
1985-1989
Spinal muscular atrophy (SMA) is a genetic disease caused by mutation or deletion of the survival motor neuron 1 (SMN1) gene. A paralogous gene in humans, SMN2, produces low, insufficient levels functional SMN protein due to alternative splicing that truncates transcript. The decreased lead progressive neuromuscular degeneration and high rates mortality. Through chemical screening optimization, we identified orally available small molecules shift balance SMN2 toward production full-length...
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...
Huntington's disease (HD) is a hereditary neurodegenerative disorder caused by expansion of cytosine-adenine-guanine (CAG) trinucleotide repeats in the huntingtin (HTT) gene. Consequently, mutant protein ubiquitously expressed and drives pathogenesis HD through toxic gain-of-function mechanism. Animal models have demonstrated that reducing levels alleviates motor neuropathological abnormalities. Investigational drugs aim to reduce HTT repressing transcription, stability or translation. These...
The thymidine analog fialuridine deoxy-2-fluoro-beta-D-arabinofuranosyl)-5-iodouracil (FIAU) was toxic in trials for chronic hepatitis B infection. One mechanism postulated that defective mtDNA replication mediated through inhibition of DNA polymerase-gamma (DNA pol-gamma), by FIAU triphosphate (FIALTP) or triphosphates metabolites. Inhibition kinetics and primer-extension analyses determined biochemical mechanisms FIAU, 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) -5-methyluracil (FAU),...
ABSTRACT The NS5B RNA-dependent RNA polymerase encoded by hepatitis C virus (HCV) plays a key role in viral replication. Reported here is evidence that HCV acts as functional oligomer. Oligomerization of protein was demonstrated gel filtration, chemical cross-linking, temperature sensitivity, and yeast cell two-hybrid analysis. Mutagenesis studies showed the C-terminal hydrophobic region not essential for its oligomerization. Importantly, exhibited cooperative synthesis activity with...
PTC299 was identified as an inhibitor of VEGFA mRNA translation in a phenotypic screen and evaluated the clinic for treatment solid tumors. To guide precision cancer treatment, we performed extensive biological characterization activity demonstrated that inhibition VEGF production cell proliferation by is linked to decrease uridine nucleotides targeting dihydroorotate dehydrogenase (DHODH), rate-limiting enzyme de novo pyrimidine nucleotide synthesis. Unlike previously reported DHODH...
Woodchucks were used to study the antiviral activity and toxicity of fialuridine (FIAU; 1,-2′deoxy-2′fluoro-1-β- d -arabinofuranosyl-5-iodo-uracil). In an initial experiment, groups six chronic woodchuck hepatitis virus (WHV) carrier woodchucks received daily doses FIAU by intraperitoneal injection for 4 weeks. At 0.3 mg/kg/d, effect was equivocal, but at 1.5 had significant activity. No evidence drug observed during 4-week period treatment or posttreatment follow-up. a second nine WHV...
To identify the minimal structural elements necessary for biological activity, rigid tricyclic nucleus of known human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) inhibitor tetrahydroimidazobenzodiazepinthione was subjected to systematic bond disconnection obtain simpler structures. A rational selection and testing modeled analogs containing these potential pharmacophoric moieties led discovery a new series nonnucleoside inhibitors RT. The lead compound this PETT RT...
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMammalian DNA Polymerases .alpha., .beta., .gamma., .delta., and .epsilon. Incorporate Fialuridine (FIAU) Monophosphate into Are Inhibited Competitively by FIAU TriphosphateWilliam Lewis, Ralph R. Meyer, James F. Simpson, Joseph M. Colacino, Fred W. PerrinoCite this: Biochemistry 1994, 33, 48, 14620–14624Publication Date (Print):December 6, 1994Publication History Published online1 May 2002Published inissue 6 December...
Current antiretroviral therapy (ART) provides potent suppression of HIV-1 replication. However, ART does not target latent viral reservoirs, so persistent infection remains a challenge. Small molecules with pharmacological properties that allow them to reach and activate reservoirs could potentially be utilized eliminate the arm when used in combination ART. Here we describe cell-based system modeling latency was high-throughput screen identify small molecule antagonists latency. A more...
A novel, potent, and orally bioavailable inhibitor of hepatitis C RNA replication targeting NS4B, compound 4t (PTC725), has been identified through chemical optimization the 6-(indol-2-yl)pyridine-3-sulfonamide 2 to improve DMPK safety properties. The focus SAR investigations identify optimal combination substituents at indole N-1, C-5, C-6 positions sulfonamide group limit potential for in vivo oxidative metabolism achieve an acceptable pharmacokinetic profile. Compound excellent potency...
Nonsense mutations resulting in a premature stop codon an open reading frame occur critical tumor suppressor genes large number of the most common forms cancers and are known to cause or contribute progression disease. Low molecular weight compounds that induce readthrough nonsense offer new means treating patients with genetic disorders from mutations. We have identified nucleoside analog clitocine as potent efficacious determined incorporation into RNA during transcription is prerequisite...
Nonsense mutations, resulting in a premature stop codon the open reading frame of mRNAs are responsible for thousands inherited diseases. Readthrough codons by small molecule drugs has emerged as promising therapeutic approach to treat disorders from termination translation. The aminoglycoside antibiotics class known promote readthrough at codons. Gentamicin consists mixture major and minor components. Here, we investigated activities individual components show that each four gentamicin...
We report the development of a human monoclonal antibody to cytomegalovirus (CMV) produced from X hybridoma. This hybrid was developed by fusion an EBV-transformed cell line making CMV and lymphoblastoid WI-L2. The is directed CMV-specific antigen primarily in nucleus CMV-infected fibroblasts. It cross-reacts with at least 10 different strains may provide method for rapid vitro diagnosis infections. production man antibodies human-human hybridomas future therapeutic use now technically...
1-(2'-Deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodocytosine (FIAC), 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-methyluridine (FMAU), 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouridine (FIAU), and 1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-ethyluridine (FEAU) were evaluated for antiviral activities against human cytomegalovirus (HCMV) compared with 9-[(2-hydroxyethoxy)methyl]guanine (acyclovir) E-5-(2'-bromovinyl)-2'-deoxyuridine (BVDU). The relative anti-HCMV...