A5034293304- Economic Theory and Institutions
- Viral Infections and Immunology Research
- Respiratory viral infections research
- RNA and protein synthesis mechanisms
- Political Philosophy and Ethics
- Synthesis and Biological Evaluation
- Photosynthetic Processes and Mechanisms
- Political Economy and Marxism
- Biochemical and Molecular Research
- Algal biology and biofuel production
- Chemical Synthesis and Analysis
- Monoclonal and Polyclonal Antibodies Research
- HIV/AIDS drug development and treatment
- Religion, Society, and Development
- American Constitutional Law and Politics
- Click Chemistry and Applications
- DNA and Nucleic Acid Chemistry
- RNA modifications and cancer
- PI3K/AKT/mTOR signaling in cancer
- interferon and immune responses
- Immune Cell Function and Interaction
- Adenosine and Purinergic Signaling
- RNA Research and Splicing
- Cancer therapeutics and mechanisms
- CRISPR and Genetic Engineering
University of Notre Dame
1978-2005
Pfizer (United States)
2001-2003
Agouron Institute
1997-2002
General Atomics (United States)
1994-2001
Australian National University
1998
University of Colorado Boulder
1995
Dana-Farber Cancer Institute
1994
Harvard University
1989-1994
University of California, Berkeley
1983-1987
Lawrence Berkeley National Laboratory
1983-1984
Human rhinoviruses, the most important etiologic agents of common cold, are messenger-active single-stranded monocistronic RNA viruses that have evolved a highly complex cascade proteolytic processing events to control viral gene expression and replication. Most maturation cleavages within precursor polyprotein mediated by rhinovirus 3C protease (or its immediate precursor, 3CD), cysteine with trypsin-like polypeptide fold. High-resolution crystal structures enzyme from three serotypes been...
Overexpression of yeast DNA topoisomerase II was achieved by placing the coding sequences gene TOP2 downstream an inducible promoter PGAL1 on a multicopy plasmid. By using simple purification procedure, milligram amounts enzyme high specific activity can be obtained from few liters culture. In presence drug VM-26 (teniposide), more than 90% molecules become covalently bound to upon addition protein denaturant sodium dodecyl sulfate. The formation covalent complex used map tyrosine residue...
ABSTRACT AG7088 is a potent, irreversible inhibitor of human rhinovirus (HRV) 3C protease {inactivation rate constant ( k obs /[I]} = 1,470,000 ± 440,000 M −1 s for HRV 14) that was discovered by protein structure-based drug design methodologies. In H1-HeLa and MRC-5 cell protection assays, inhibited the replication all serotypes (48 48) tested with mean 50% effective concentration (EC 50 ) 0.023 μM (range, 0.003 to 0.081 μM) EC 90 0.082 0.018 0.261 as well related picornaviruses including...
The structure-based design, chemical synthesis, and biological evaluation of various human rhinovirus (HRV) 3C protease (3CP) inhibitors which incorporate P1 lactam moieties in lieu an L-glutamine residue are described. These compounds comprised a tripeptidyl or peptidomimetic binding determinant ethyl propenoate Michael acceptor moiety forms irreversible covalent adduct with the active site cysteine enzyme. P1-lactam-containing display significantly increased 3CP inhibition activity along...
The design, synthesis, and biological evaluation of reversible, nonpeptidic inhibitors human rhinovirus (HRV) 3C protease (3CP) are reported. A novel series 2,3-dioxindoles (isatins) were designed that utilized a combination protein structure-based drug molecular modeling, structure-activity relationship (SAR). C-2 carbonyl isatin was envisioned to react in the active site HRV 3CP with cysteine responsible for catalytic proteolysis, thus forming stabilized transition state mimic....
The structure-based design, chemical synthesis, and biological evaluation of various 2-pyridone-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds comprised a peptidomimetic binding determinant Michael acceptor moiety, which forms an irreversible covalent adduct with the active site cysteine residue enzyme. typically display improved 3CP inhibition properties relative to related peptide-derived molecules along more favorable antiviral properties....
The structure-based design, chemical synthesis, and biological evaluation of various peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds comprised an ethyl propenoate Michael acceptor moiety a tripeptidyl binding determinant. systematic modification each amino acid residue present in the determinant as well N-terminal functionality is Such modifications shown to provide irreversible HRV-14 3CP with anti-3CP activities (kobs/[I]) ranging from 60...
The structure-based design, chemical synthesis, and biological evaluation of peptide-derived human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds incorporate various Michael acceptor moieties shown to irreversibly bind HRV serotype 14 3CP with inhibition activities (kobs/[I]) ranging from 100 600 000 M-1 s-1. also exhibit antiviral activity when tested against HRV-14-infected H1-HeLa cells EC50's approaching 0.50 μM. Extensive structure−activity relationships...
The investigation of tripeptide aldehydes as reversible covalent inhibitors human rhinovirus (HRV) 3C protease (3CP) is reported. Molecular models based on the apo crystal structure HRV-14 3CP and other trypsin-like serine proteases were constructed to approximate binding peptide substrates, generate transition state P1-P1' amide cleavage, propose novel aldehydes. Glutaminal derivatives have limitations since they exist predominantly in cyclic hemiaminal form. Therefore, several isosteric...
The structure-based design, chemical synthesis, and biological evaluation of various ketomethylene-containing human rhinovirus (HRV) 3C protease (3CP) inhibitors are described. These compounds comprised a peptidomimetic binding determinant an ethyl propenoate Michael acceptor moiety which forms irreversible covalent adduct with the active site cysteine residue enzyme. typically display slightly reduced 3CP inhibition activity relative to corresponding peptide-derived molecules, but they also...
Symptom severity in patients with human rhinovirus (HRV)-induced respiratory illness is associated elevated levels of the inflammatory cytokines interleukin-6 (IL-6) and IL-8. AG7088 a novel, irreversible inhibitor HRV 3C protease. In this study, was tested for its antiviral activity ability to inhibit production IL-6 IL-8 bronchial epithelial cell line, BEAS-2B. Infection BEAS-2B cells 14 resulted both infectious virus Treatment 14-infected statistically significant (P, <0.05)...
A series of nonpeptide benzamide-containing inhibitors human rhinovirus (HRV) 3C protease was identified using structure-based design. The design, synthesis, and biological evaluation these are reported. Michael acceptor combined with a benzamide core mimicking the P1 recognition element natural 3CP substrate. alpha,beta-Unsaturated cinnamate esters irreversibly inhibited displayed antiviral activity (EC(50) 0.60 microM, HRV-16 infected H1-HeLa cells). On basis cocrystal structure...
Utilizing the tools of parallel synthesis and structure-based design, a new class Michael acceptor-containing, irreversible inhibitors human rhinovirus 3C protease (HRV 3CP) was discovered. These are shown to inhibit HRV-14 3CP with rates inactivation ranging from 886 31 400 M-1 sec-1. exhibit antiviral activity when tested against infected H1-HeLa cells, EC50 values 1.94 0.15 μM. No cytotoxicity observed at limits assay concentration. A crystal structure one more potent covalently bound...
Journal Article S. T. Worland. Scholasticism and Welfare Economics Get access Economics. By (Notre Dame: University of Notre Dame Press, 1967. Pp. x + 297. 56s.) W. Hutchison Birmingham. Search for other works by this author on: Oxford Academic Google Scholar The Economic Journal, Volume 78, Issue 311, 1 September 1968, Pages 668–669, https://doi.org/10.2307/2229392 Published: 01 1968
Highlights•Genome-wide CRISPRi screen reveals more than 600 synthetic lethal partners of eIF4E•Functional interaction between eIF4E and Bcl-xL is important for tumor growth•Mitochondrial dysfunction triggers an eIF4E-dependent adaptive stress response•Interaction EJC controls the migratory capacity cancer cellsSummaryThe major cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), ancient required all genomes, a surprising yet potent oncogenic driver. The genetic...