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| Content Provider | World Health Organization (WHO)-Global Index Medicus |
|---|---|
| Author | Frassineti, Chiara Luciani, Rosaria Marverti, Gaetano Mangani, Stefano Guerrieri, Davide Tondi, Donatella Ligabue, Alessio Salo-ahen, Outi M. H. Guerrini, Remo Pozzi, Cecilia Ponterini, Glauco Costi, M. Paola Ferrari, Stefania Wade, Rebecca C. Cardinale, Daniela Guaitoli, Giambattista Henrich, Stefan Fessas, Dimitrios |
| Description | Author Affiliation: Cardinale D ( Department of Pharmaceutical Sciences, via Campi 183, University of Modena and Reggio Emilia, 41126 Modena, Italy.); |
| Abstract | Human thymidylate synthase is a homodimeric enzyme that plays a key role in DNA synthesis and is a target for several clinically important anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The 'LR' peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer. |
| ISSN | 00278424 |
| e-ISSN | 10916490 |
| Journal | Proceedings of the National Academy of Sciences of the United States of America |
| Issue Number | 34 |
| Volume Number | 108 |
| Language | English |
| Publisher | National Academy of Sciences |
| Publisher Date | 2011-08-01 |
| Publisher Place | United States |
| Access Restriction | Open |
| Subject Keyword | Enzyme Inhibitors Pharmacology Molecular Targeted Therapy Ovarian Neoplasms Enzymology Peptides Metabolism Thymidylate Synthase Antagonists & Inhibitors Amino Acid Sequence Binding Sites Cell Line, Tumor Cell Proliferation Drug Effects Cisplatin Therapeutic Use Crystallography, X-Ray Drug Design Chemistry Fluorouracil Kinetics Models, Molecular Molecular Sequence Data Drug Therapy Pathology Protein Binding Protein Conformation Protein Multimerization Thermodynamics Research Support, Non-U.S. Gov't Multidisciplinary |
| Content Type | Text |
| Resource Type | Article |
| Subject | Multidisciplinary |
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