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.
Puneet Saxena  1 ,  Leda Severi  1 ,  Matteo Santucci  1 ,  Laura Taddia  1 ,  Stefania Ferrari  1 ,  Rosaria Luciani  1 ,  Gaetano Marverti  2 ,  Chiara Marraccini  1 ,  Donatella Tondi  1 ,  Marco Mor  3 ,  Laura Scalvini  3 ,  Simone Vitiello  1 ,  Lorena Losi  1  4 ,  Sergio Fonda  1 ,  Salvatore Pacifico  5 ,  Remo Guerrini  5  6 ,  Domenico D'Arca  2 ,  Glauco Ponterini  1 ,  Maria Paola Costi  1
Affiliations
  • 1. Department of Life Sciences , University of Modena and Reggio Emilia , Via Campi 103 , 41125 Modena , Italy.
  • 2. Department of Biomedical Sciences, Metabolic and Neural Sciences , University of Modena and Reggio Emilia , Via Campi 287 , 41125 Modena , Italy.
  • 3. Dipartimento di Scienze degli Alimenti e del Farmaco , Università di Parma , Parco Area delle Scienze 27/A , I-43124 Parma , Italy.
  • 4. Pathological Anatomy , Via del Pozzo 71 , 41124 Modena , Italy.
  • 5. Department of Chemical and Pharmaceutical Sciences , University of Ferrara , Via Luigi Borsari 46 , 44121 Ferrara , Italy.
  • 6. LTTA (Laboratorio per le Tecnologie delle Terapie Avanzate) , Via Fossato di Mortara 17-19 , 44100 Ferrara , Italy.
PMID: 30035541 DOI: 10.1021/acs.jmedchem.7b01699
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.