A5028372834- HIV/AIDS drug development and treatment
- HIV Research and Treatment
- Biochemical and Molecular Research
- Influenza Virus Research Studies
- DNA and Nucleic Acid Chemistry
- Enzyme Structure and Function
- RNA and protein synthesis mechanisms
- Viral Infections and Immunology Research
- interferon and immune responses
- Computational Drug Discovery Methods
- Protein Structure and Dynamics
- Click Chemistry and Applications
- Cytokine Signaling Pathways and Interactions
- HIV/AIDS Research and Interventions
- RNA Research and Splicing
- Synthesis and biological activity
- Tuberculosis Research and Epidemiology
- Spectroscopy and Quantum Chemical Studies
- Respiratory viral infections research
- Hepatitis C virus research
- Protein Kinase Regulation and GTPase Signaling
- Microbial Natural Products and Biosynthesis
- Cancer Treatment and Pharmacology
- Polyomavirus and related diseases
- HIV-related health complications and treatments
Rutgers, The State University of New Jersey
2013-2023
Advanced Pharma
2008-2022
Quantitative BioSciences
2011
University of Pittsburgh
2011
Rütgers (Germany)
2010
Rutgers Sexual and Reproductive Health and Rights
2010
University of South Carolina Sumter
2008
Joint Base San Antonio
1985
Brooke Army Medical Center
1985
Fitzsimons Army Medical Center
1985
TMC278 is a diarylpyrimidine (DAPY) nonnucleoside reverse transcriptase inhibitor (NNRTI) that highly effective in treating wild-type and drug-resistant HIV-1 infections clinical trials at relatively low doses ( approximately 25-75 mg/day). We have determined the structure of RT complexed with 1.8 A resolution, using an crystal form engineered by systematic mutagenesis. This high-resolution reveals cyanovinyl group positioned hydrophobic tunnel connecting NNRTI-binding pocket to nucleic...
The two nitrile groups at the wings of nonnucleoside HIV-1 reverse transcriptase (RT) inhibitor TMC278 are both identified in high-sensitivity 2D IR spectroscopy experiments RT/TMC278 complex. vibrational spectra indicate that arms sense quite different environments within hydrophobic pocket. relaxation almost equal 3 ps from model studies. expose a significant distribution frequencies diffuse equilibrium on ultrafast time scales ranging hundreds femtoseconds to tens picoseconds. slow...
HIV-1 reverse transcriptase (RT) undergoes a series of conformational changes during viral replication and is central target for antiretroviral therapy. The intrinsic flexibility RT can provide novel allosteric sites inhibition. Crystals that diffract X-rays to better than 2 Å resolution facilitated the probing new druggable using fragment screening by X-ray crystallography. A total 775 fragments were grouped into 143 cocktails, which soaked crystals in complex with non-nucleoside drug...
Seasonal and pandemic influenza viruses continue to be a leading global health concern. Emerging resistance the current drugs variable efficacy of vaccines underscore need for developing new flu that will broadly effective against wild-type drug-resistant strains. Here, we report discovery development class inhibitors targeting cap-snatching endonuclease activity viral polymerase. A high-resolution crystal form 2009 H1N1 polymerase acidic protein N-terminal domain (PAN) was engineered used...
The α-hydroxytroplone, manicol (5,7-dihydroxy-2-isopropenyl-9-methyl-1,2,3,4-tetrahydro-benzocyclohepten-6-one), potently and specifically inhibits ribonuclease H (RNase H) activity of human immunodeficiency virus reverse transcriptase (HIV RT) in vitro. However, was ineffective reducing replication culture. Ongoing efforts to improve the potency specificity over lead compound led us synthesize 14 derivatives that retain divalent metal-chelating α-hydroxytropolone pharmacophore. These were...
HIV-1 reverse transcriptase (RT) is a primary target for anti-AIDS drugs. Structures of RT, usually determined at ∼2.5–3.0 Å resolution, are important understanding enzyme function and mechanisms drug resistance in addition to being helpful the design RT inhibitors. Despite hundreds attempts, it was not possible obtain structure complex with TMC278, nonnucleoside inhibitor (NNRTI) advanced clinical trials. A systematic iterative protein crystal engineering approach developed optimize...
tert-Butyldimethylsilyl-spiroaminooxathioledioxide (TSAO) compounds have an embedded thymidine-analogue backbone; however, TSAO invoke non-nucleoside RT inhibitor (NNRTI) resistance mutations. Our crystal structure of RT:7 (TSAO-T) complex shows that 7 binds inside the NNRTI-binding pocket, assuming a "dragon" shape, and interacts extensively with almost all pocket residues. The also explains structure-activity relationships data for compounds. binding causes hyper-expansion significant...
Seasonal and pandemic influenza outbreaks remain a major human health problem. Inhibition of the endonuclease activity RNA-dependent RNA polymerase is attractive for development new agents treatment infection. Our earlier studies identified series 5- 6-phenyl substituted 3-hydroxypyridin-2(1H)-ones that were effective inhibitors endonuclease. These as bimetal chelating ligands binding to active site enzyme. In present study, several aza analogues these phenyl 3-hydroxypyridin-2(1H)-one...
The enzyme guanylyltransferase (GTase) plays a central role in the three-step catalytic process of adding an m7 GpppN cap cotranscriptionally to nascent mRNA (pre-mRNAs). 5′-mRNA capping is functionally and evolutionarily conserved from unicellular organisms human. However, GTases viruses yeast have low amino acid sequence identity (∼25%) with mammals that, contrast, are highly (∼98%). We defined by limited proteolysis human residues 229–567 as comprising minimum enzymatically active GTase...
Several 3-hydroxyquinolin-2(1H)-ones derivatives were synthesized and evaluated as inhibitors of 2009 pandemic H1N1 influenza A endonuclease. All five the monobrominated 3-hydroxyquinolin(1H)-2-ones synthesized. Suzuki-coupling p-fluorophenylboronic acid with each these brominated provided respective p-fluorophenyl 3-hydroxyquinolin(1H)-2-ones. In addition to 3-hydroxyquinolin-2(1H)-one, its 4-methyl, 4-phenyl, 4-methyl-7-(p-fluorophenyl), 4-phenyl-7-(p-fluorophenyl) also Comparative studies...
X-ray crystallographic fragment screening (XCFS) uses fragment-sized molecules (∼60 to 300 Da) access binding sites on proteins that may be inaccessible larger drug-like (>300 Da). Previous studies have shown fragments containing halogen atoms bind more often than non-halogenated fragments. Here, we designed the Halo Library 46 halogenated (including "universal fragment" 4-bromopyrazole), a majority of which been reported or inhibit one targets. The library was screened against crystals...
Several cap-binding proteins from both the nucleus and cytosol have been identified that mediate processes such as pre-mRNA splicing, translation initiation, mRNA turnover. Here we describe a novel protein, pokeweed antiviral protein (PAP), 29-kDa type I ribosome-inactivating (RIP) isolated Phytolacca americana. In addition to depurinating sarcin/ricin loop of large rRNA, an activity common all RIPs, reported recently PAP depurinates capped, but not uncapped RNAs in vitro. characterize this...
The ribonuclease H (RNase H) domain on the p66 monomer of HIV-1 reverse transcriptase enzyme has become a target for inhibition. active site is one potential binding site, but other RNase sites can accommodate inhibitors. Using combination experimental and computational studies, new modes have been identified. Libraries compounds were screened with an assay to identify actives without knowledge site. computationally docked at putative sites. Based positive enrichment natural-product relative...
Abstract Background The recently approved anti-AIDS drug rilpivirine (TMC278, Edurant) is a nonnucleoside inhibitor (NNRTI) that binds to reverse transcriptase (RT) and allosterically blocks the chemical step of DNA synthesis. In contrast earlier NNRTIs, retains potency against well-characterized, clinically relevant RT mutants. Many structural analogues are described in patent literature, but detailed analyses their antiviral activities have not been published. This work addresses ability...
Through X-ray crystallographic fragment screening, 4-bromopyrazole was discovered to be a 'magic bullet' that is capable of binding at many the ligand 'hot spots' found in HIV-1 reverse transcriptase (RT). The locations can pockets are 'hidden' unliganded crystal form, allowing rapid identification these sites for silico screening. In addition hot-spot identification, this ubiquitous yet specific provides an avenue phase determination, which significant bottleneck determination structures...
Key proteins of retroviruses and other RNA viruses are translated subsequently processed from polyprotein precursors by the viral protease (PR). Processing HIV Gag-Pol yields structural enzymes. Structures mature enzymes PR, reverse transcriptase (RT), integrase (IN) aided understanding catalysis design antiretrovirals, but knowledge Pol precursor architecture function before PR cleavage is limited. We developed a system to produce stable HIV-1 determined its cryo–electron microscopy...
Human immunodeficiency virus type I (HIV-1) is a retrovirus that infects cells of the host's immune system leading to acquired syndrome and potentially death. Although treatments are available prevent its progression, HIV-1 remains major burden on health resources worldwide. Continued emergence drug-resistance mutations drives need for novel drugs can inhibit replication through new pathways. The viral protein reverse transcriptase (RT) plays fundamental role in cycle, multiple approved...