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Articles 1 - 6 of 6
Full-Text Articles in Biochemistry, Biophysics, and Structural Biology
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Evolution Of The Influenza A Virus Genome During Development Of Oseltamivir Resistance In Vitro, Nicholas Renzette, Daniel R. Caffrey, Konstantin B. Zeldovich, Ping Liu, Glen R. Gallagher, Daniel Aiello, Alyssa J. Porter, Evelyn A. Kurt-Jones, Daniel N. Bolon, Yu-Ping Poh, Jeffrey D. Jensen, Celia A. Schiffer, Timothy F. Kowalik, Robert W. Finberg, Jennifer P. Wang
Celia A. Schiffer
Influenza A virus (IAV) is a major cause of morbidity and mortality throughout the world. Current antiviral therapies include oseltamivir, a neuraminidase inhibitor that prevents the release of nascent viral particles from infected cells. However, the IAV genome can evolve rapidly, and oseltamivir resistance mutations have been detected in numerous clinical samples. Using an in vitro evolution platform and whole-genome population sequencing, we investigated the population genomics of IAV during the development of oseltamivir resistance. Strain A/Brisbane/59/2007 (H1N1) was grown in Madin-Darby canine kidney cells with or without escalating concentrations of oseltamivir over serial passages. Following drug treatment, the H274Y …
Therapeutic Targeting Of C-Terminal Binding Protein In Human Cancer, Michael W. Straza, Seema Paliwal, Ramesh C. Kovi, Barur R. Rajeshkumar, Peter Trenh, Daniel Parker, Giles F. Whalen, Stephen Lyle, Celia A. Schiffer, Steven R. Grossman
Therapeutic Targeting Of C-Terminal Binding Protein In Human Cancer, Michael W. Straza, Seema Paliwal, Ramesh C. Kovi, Barur R. Rajeshkumar, Peter Trenh, Daniel Parker, Giles F. Whalen, Stephen Lyle, Celia A. Schiffer, Steven R. Grossman
Celia A. Schiffer
The CtBP transcriptional corepressors promote cancer cell survival and migration/invasion. CtBP senses cellular metabolism via a regulatory dehydrogenase domain, and is antagonized by p14/p19(ARF) tumor suppressors. The CtBP dehydrogenase substrate 4-methylthio-2-oxobutyric acid (MTOB) can act as a CtBP inhibitor at high concentrations, and is cytotoxic to cancer cells. MTOB induced apoptosis was p53-independent, correlated with the derepression of the proapoptotic CtBP repression target Bik, and was rescued by CtBP overexpression or Bik silencing. MTOB did not induce apoptosis in mouse embryonic fibroblasts (MEFs), but was increasingly cytotoxic to immortalized and transformed MEFs, suggesting that CtBP inhibition may provide a suitable …
Accounting For Molecular Mobility In Structure Determination Based On Nuclear Magnetic Resonance Spectroscopic And X-Ray Diffraction Data, Wilfred Van Gunsteren, Roger Brunne, P. Gros, René Van Schaik, Celia Schiffer, Andrew Torda
Accounting For Molecular Mobility In Structure Determination Based On Nuclear Magnetic Resonance Spectroscopic And X-Ray Diffraction Data, Wilfred Van Gunsteren, Roger Brunne, P. Gros, René Van Schaik, Celia Schiffer, Andrew Torda
Celia A. Schiffer
No abstract provided.
Design Of Hiv-1 Protease Inhibitors Active On Multidrug-Resistant Virus, Dominique Surleraux, Herman De Kock, Wim Verschueren, Geert Pille, Louis Maes, Anik Peeters, Sandrine Vendeville, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Design Of Hiv-1 Protease Inhibitors Active On Multidrug-Resistant Virus, Dominique Surleraux, Herman De Kock, Wim Verschueren, Geert Pille, Louis Maes, Anik Peeters, Sandrine Vendeville, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Celia A. Schiffer
On the basis of structural data gathered during our ongoing HIV-1 protease inhibitors program, from which our clinical candidate TMC114 9 was selected, we have discovered new series of fused heteroaromatic sulfonamides. The further extension into the P2' region was aimed at identifying new classes of compounds with an improved broad spectrum activity and acceptable pharmacokinetic properties. Several of these compounds display an exceptional broad spectrum activity against a panel of highly cross-resistant mutants. Certain members of these series exhibit favorable pharmacokinetic profiles in rat and dog. Crystal structures and molecular modeling were used to rationalize the broad spectrum profile …
Prediction Of Homologous Protein Structures Based On Conformational Searches And Energetics, Celia Schiffer, James Caldwell, Peter Kollman, Robert Stroud
Prediction Of Homologous Protein Structures Based On Conformational Searches And Energetics, Celia Schiffer, James Caldwell, Peter Kollman, Robert Stroud
Celia A. Schiffer
A "knowledge-based" method of predicting the unknown structure of a protein from a homologous known structure using energetics to determine a sidechain conformation is proposed. The method consists of exchanging the residues in the known structure for the sequence of the unknown protein. Then a conformational search with molecular mechanics energy minimization is done on the exchanged residues. The lowest energy conformer is the one picked to be the predicted structure. In the structure of bovine trypsin, the importance of including a solvation energy term in the search is demonstrated for solvent accessible residues, while molecular mechanics alone is enough …
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Discovery And Selection Of Tmc114, A Next Generation Hiv-1 Protease Inhibitor, Dominique Surleraux, Abdellah Tahri, Wim Verschueren, Geert Pille, Herman De Kock, Tim Jonckers, Anik Peeters, Sandra De Meyer, Hilde Azijn, Rudi Pauwels, Marie-Pierre De Bethune, Nancy King, Moses Prabu-Jeyabalan, Celia Schiffer, Piet Wigerinck
Celia A. Schiffer
The screening of known HIV-1 protease inhibitors against a panel of multi-drug-resistant viruses revealed the potent activity of TMC126 on drug-resistant mutants. In comparison to amprenavir, the improved affinity of TMC126 is largely the result of one extra hydrogen bond to the backbone of the protein in the P2 pocket. Modification of the substitution pattern on the phenylsulfonamide P2' substituent of TMC126 created an interesting SAR, with the close analogue TMC114 being found to have a similar antiviral activity against the mutant and the wild-type viruses. X-ray and thermodynamic studies on both wild-type and mutant enzymes showed an extremely high …