A5048319542- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Biochemical and Molecular Research
- Pneumocystis jirovecii pneumonia detection and treatment
- Parasitic Infections and Diagnostics
- Enzyme Structure and Function
- HIV/AIDS Research and Interventions
- Synthesis and Characterization of Heterocyclic Compounds
- Tuberculosis Research and Epidemiology
- Computational Drug Discovery Methods
- Immunotherapy and Immune Responses
- Radiomics and Machine Learning in Medical Imaging
- Fibroblast Growth Factor Research
- Lung Cancer Treatments and Mutations
- RNA modifications and cancer
- Cytomegalovirus and herpesvirus research
- DNA and Nucleic Acid Chemistry
- Click Chemistry and Applications
- Epigenetics and DNA Methylation
- HER2/EGFR in Cancer Research
- Cervical Cancer and HPV Research
- Cancer Genomics and Diagnostics
- Synthesis and biological activity
- Advanced Breast Cancer Therapies
- SARS-CoV-2 and COVID-19 Research
Yale University
2016-2025
Yale Cancer Center
2019-2025
Arizona State University
2015-2025
Emissions Reduction Alberta
2024
Georgetown University
2022
University of Ulster
2018
Belfast City Hospital
2018
University of New Haven
2013-2018
Mayo Clinic in Florida
2017
WinnMed
2017
The mechanism of inhibition HIV-1 reverse transcriptase by three nonnucleoside inhibitors is described. Nevirapine, O-TIBO, and CI-TIBO each bind to a hydrophobic pocket in the enzyme-DNA complex close active site catalytic residues. Pre-steady-state kinetic analysis was used establish these noncompetitive inhibitors. Analysis pre-steady-state burst DNA polymerization indicated that blocked chemical reaction, but did not interfere with nucleotide binding or nucleotide-induced conformational...
We have examined the RNA-dependent and DNA-dependent polymerase ribonuclease H catalytic activities of human immunodeficiency virus reverse transcriptase using rapid transient kinetic methods with defined synthetic 25/45-mer DNA/RNA DNA/DNA primer/templates. The Kd value for interaction enzyme duplex DNA was 4.7 nM, RNA/DNA heteroduplex similar magnitude. A pre-steady state burst nucleoside triphosphate incorporation observed both RNA templates. Analysis dATP concentration dependence rate...
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...
Starting from our previous finding of 14 known drugs as inhibitors the main protease (Mpro) SARS-CoV-2, virus responsible for COVID-19, we have redesigned weak hit perampanel to yield multiple noncovalent, nonpeptidic with ca. 20 nM IC50 values in a kinetic assay. Free-energy perturbation (FEP) calculations Mpro-ligand complexes provided valuable guidance on beneficial modifications that rapidly delivered potent analogues. The design efforts were confirmed and augmented by determination...
A consensus virtual screening protocol has been applied to ca. 2000 approved drugs seek inhibitors of the main protease (Mpro) SARS-CoV-2, virus responsible for COVID-19. 42 emerged as top candidates, and after visual analyses predicted structures their complexes with Mpro, 17 were chosen evaluation in a kinetic assay Mpro inhibition. Remarkably 14 compounds at 100-μM concentration found reduce enzymatic activity 5 provided IC50 values below 40 μM: manidipine (4.8 μM), boceprevir (5.4...
We have investigated the role of putative peptide transporters associated with antigen processing (TAP) by using a permeabilized-cell system. The main objective was to determine whether these molecules, which bear homology ATP-binding cassette family transporters, translocate antigenic peptides across endoplasmic reticulum membrane for assembly major histocompatibility complex (MHC) class I molecules and beta 2-microglobulin light chain. pore-forming toxin streptolysin O used generate...
The HLA-A2-positive human mutant cell line T2 is not lysed by influenza virus-specific HLA-A2-restricted cytotoxic lymphocytes after virus infection. However, lysis does occur when cells are incubated with the antigenic matrix protein-derived peptide M57-68. To examine nature of this defect, were transfected two different plasmids. One plasmid encoded M57-68, and other same preceded an endoplasmic reticulum translocation signal sequence. Mutant expressing M57-68 without sequence susceptible...
Abstract Somatic mutations within the epidermal growth factor receptor (EGFR) kinase domain are detected in 10% to 30% of human non–small cell lung cancers and correlated with striking clinical responses a subset patients treated EGFR inhibitors, such as gefitinib erlotinib. Cell-based studies suggest that these mutant EGFRs promote increased autophosphorylating activity on COOH-terminal tyrosines consequent engagement downstream effectors. Because function is regulated at multiple levels...
Tryptophan synthase, an alpha 2 beta complex, is a classic example of enzyme that thought to channel metabolic intermediate (indole) from the active site subunit subunit. We now examine kinetics substrate channeling by tryptophan synthase directly chemical quench-flow and stopped-flow methods. The conversion indole-3-glycerol phosphate (IGP) at proceeds rate 24 s-1, which limited cleavage IGP produce indole (alpha reaction). In single turnover experiment monitoring radiolabeled tryptophan,...
The order of FGFR1 tyrosine autophosphorylation is kinetically controlled and determined by primary tertiary structures.
Abstract Access to experimental X-ray diffraction image data is fundamental for validation and reproduction of macromolecular models indispensable development structural biology processing methods. Here, we established a publication dissemination system, Structural Biology Data Grid (SBDG; data.sbgrid.org), preserve primary sets that support scientific publications. are accessible researchers through community driven grid, which facilitates global access. Our analysis pilot collection...
A 5-μM docking hit has been optimized to an extraordinarily potent (55 pM) non-nucleoside inhibitor of HIV reverse transcriptase. Use free energy perturbation (FEP) calculations predict relative energies binding aided the optimizations by identifying optimal substitution patterns for phenyl rings and a linker. The most resultant catechol diethers feature terminal uracil cyanovinylphenyl groups. halogen bond with Pro95 likely contributes extreme potency compound 42. In addition, several...
Members of the catechol diether class are highly potent non-nucleoside inhibitors HIV-1 reverse transcriptase (NNRTIs). The most active compounds yield EC50 values below 0.5 nM in assays using human T-cells infected by wild-type HIV-1. However, these such as rilpivirine, recently FDA-approved NNRTI, bear a cyanovinylphenyl (CVP) group. This is an uncommon substructure drugs that gives reactivity concerns. In present work, computer simulations were used to design bicyclic replacements for CVP...
Recent studies have revealed the mutational signatures underlying somatic evolution of cancer, and prevalences associated genetic variants. Here we estimate intensity positive selection that drives mutations to high frequency in tumors, yielding higher than expected on basis mutation neutral drift alone. We apply this approach a sample 525 head neck squamous cell carcinoma exomes, producing rank-ordered list gene variants by intensity. Our results illustrate complementarity calculating along...
As the SARS-CoV-2 virus continues to spread and mutate, it remains important focus not only on preventing through vaccination but also treating infection with direct-acting antivirals (DAA). The approval of Paxlovid, a main protease (M pro ) DAA, has been significant for treatment patients. A limitation this however, is that antiviral component, nirmatrelvir, rapidly metabolized requires inclusion CYP450 3A4 metabolic inhibitor, ritonavir, boost levels active drug. Serious drug–drug...
5-enol-Pyruvylshikimate-3-phosphate synthase (EPSP synthase; phosphoenolpyruvate:3-phosphoshikimate 1-carboxyvinyltransferase, EC 2.5.1.19) is an enzyme on the pathway toward synthesis of aromatic amino acids in plants, fungi, and bacteria target broad-spectrum herbicide glyphosate. The three-dimensional structure from Escherichia coli has been determined by crystallographic techniques. polypeptide backbone chain was traced examination electron density map calculated at 3-A resolution....
ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTA tetrahedral intermediate in the EPSP synthase reaction observed by rapid quench kineticsKaren S. Anderson, James A. Sikorski, and Kenneth JohnsonCite this: Biochemistry 1988, 27, 19, 7395–7406Publication Date (Print):September 1, 1988Publication History Published online1 May 2002Published inissue 1 September 1988https://pubs.acs.org/doi/10.1021/bi00419a034https://doi.org/10.1021/bi00419a034research-articleACS PublicationsRequest reuse...