Conformational Propensity and Biological Studies of Proline Mutated LR Peptides Inhibiting Human Thymidylate Synthase and Ovarian Cancer Cell Growth.

Abstract

LR and [d-Gln4]LR peptides bind the monomer-monomer interface of human thymidylate synthase and inhibit cancer cell growth. Here, proline-mutated LR peptides were synthesized. Molecular dynamics calculations and circular dichroism spectra have provided a consistent picture of the conformational propensities of the [Pro n]-peptides. [Pro3]LR and [Pro4]LR show improved cell growth inhibition and similar intracellular protein modulation compared with LR. These represent a step forward to the identification of more rigid and metabolically stable peptides.

• Authors: Puneet Saxena, Leda Severi, Matteo Santucci, Laura Taddia, Stefania Ferrari, Rosaria Luciani, Gaetano Marverti, Chiara Marraccini, Donatella Tondi, Marco Mor, Laura Scalvini, Simone Vitiello, Lorena Losi, Sergio Fonda, Salvatore Pacifico, Remo Guerrini, Domenico D'Arca, Glauco Ponterini, Maria Paola Costi
• Journal: Journal of medicinal chemistry (J Med Chem) Vol. 61 Issue 16 Pg. 7374-7380 (08 23 2018) ISSN: 1520-4804 [Electronic] United States
• PMID: 30035541 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Enzyme Inhibitors
• Peptides
• Proline
• Thymidylate Synthase

Topics

• Antineoplastic Agents (chemistry, pharmacology)
• Cell Line, Tumor
• Circular Dichroism
• Enzyme Inhibitors (chemistry, pharmacology)
• Female
• Humans
• Molecular Dynamics Simulation
• Mutation
• Ovarian Neoplasms (drug therapy, pathology)
• Peptides (chemistry, genetics, pharmacology)
• Proline (genetics)
• Protein Conformation
• Thymidylate Synthase (antagonists & inhibitors, genetics, metabolism)