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

J Med Chem. 2018 Aug 23;61(16):7374-7380. doi: 10.1021/acs.jmedchem.7b01699. Epub 2018 Aug 13.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

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

Substances

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