Optimization of peptides that target human thymidylate synthase to inhibit ovarian cancer cell growth
Autor: | Michela Pela, Gaetano Marverti, Maria Paola Costi, Filippo Genovese, Chiara Marraccini, Andrea Martello, Glauco Ponterini, Silvia Pirondi, Domenico D'Arca, Puneet Saxena, Stefania Ferrari, Remo Guerrini, Rosaria Luciani, Severo Salvadori, Matteo Santucci |
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Rok vydání: | 2014 |
Předmět: |
Protein Conformation
ovarian cancer thymidylate synthase oligopeptides enzyme inhibition drug lead optimization Peptide Molecular Dynamics Simulation Thymidylate synthase Polymerase Chain Reaction Protein structure Cell Line Tumor Drug Discovery Dihydrofolate reductase Humans chemistry.chemical_classification Ovarian Neoplasms Oligopeptide Crystallography biology Cell growth Circular Dichroism Thymidylate Synthase Prodrug Molecular biology Biochemistry chemistry Cell culture biology.protein Molecular Medicine Female Peptides Cell Division |
Zdroj: | Journal of medicinal chemistry. 57(4) |
ISSN: | 1520-4804 |
Popis: | Thymidylate synthase (TS) is a target for pemetrexed and the prodrug 5-fluorouracil (5-FU) that inhibit the protein by binding at its active site. Prolonged administration of these drugs causes TS overexpression, leading to drug resistance. The peptide lead, LR (LSCQLYQR), allosterically stabilizes the inactive form of the protein and inhibits ovarian cancer (OC) cell growth with stable TS and decreased dihydrofolate reductase (DHFR) expression. To improve TS inhibition and the anticancer effect, we have developed 35 peptides by modifying the lead. The d-glutamine-modified peptide displayed the best inhibition of cisplatin-sensitive and -resistant OC cell growth, was more active than LR and 5-FU, and showed a TS/DHFR expression pattern similar to LR. Circular dichroism spectroscopy and molecular dynamics studies provided a molecular-level rationale for the differences in structural preferences and the enzyme inhibitory activities. By combining target inhibition studies and the modulation pattern of associated proteins, this work avenues a concept to develop more specific inhibitors of OC cell growth and drug leads. |
Databáze: | OpenAIRE |
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