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Cyclic Peptides Acting as Allosteric Inhibitors of Human Thymidylate Synthase and Cancer Cell Growth.
Pacifico, Salvatore; Santucci, Matteo; Luciani, Rosaria; Saxena, Puneet; Linciano, Pasquale; Ponterini, Glauco; Lauriola, Angela; D'Arca, Domenico; Marverti, Gaetano; Guerrini, Remo; Costi, Maria Paola.
Afiliação
  • Pacifico S; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy. salvatore.pacifico@unife.it.
  • Santucci M; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 103, 41125 Modena, Italy. matteo.santucci86@gmail.com.
  • Luciani R; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 103, 41125 Modena, Italy. rosaria.luciani@libero.it.
  • Saxena P; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 103, 41125 Modena, Italy. puneet_saxena07@yahoo.com.
  • Linciano P; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 103, 41125 Modena, Italy. pasquale.linciano@unimore.it.
  • Ponterini G; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 103, 41125 Modena, Italy. glauco.ponterini@unimore.it.
  • Lauriola A; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 103, 41125 Modena, Italy. angela.lauriola@unimore.it.
  • D'Arca D; Department of Biomedical Sciences, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy. domenico.darca@unimore.it.
  • Marverti G; Department of Biomedical Sciences, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, via Campi 287, 41125 Modena, Italy. gaetano.marverti@unimore.it.
  • Guerrini R; Department of Chemical and Pharmaceutical Sciences, University of Ferrara, via Fossato di Mortara 17-19, 44100 Ferrara, Italy. remo.guerrini@unife.it.
  • Costi MP; Department of Life Sciences, University of Modena and Reggio Emilia, via Campi, 103, 41125 Modena, Italy. mariapaola.costi@unimore.it.
Molecules ; 24(19)2019 Sep 26.
Article em En | MEDLINE | ID: mdl-31561530
ABSTRACT
Thymidylate synthase (TS) is a prominent drug target for different cancer types. However, the prolonged use of its classical inhibitors, substrate analogs that bind at the active site, leads to TS overexpression and drug resistance in the clinic. In the effort to identify anti-TS drugs with new modes of action and able to overcome platinum drug resistance in ovarian cancer, octapeptides with a new allosteric inhibition mechanism were identified as cancer cell growth inhibitors that do not cause TS overexpression. To improve the biological properties, 10 cyclic peptides (cPs) were designed from the lead peptides and synthesized. The cPs were screened for the ability to inhibit recombinant human thymidylate synthase (hTS), and peptide 7 was found to act as an allosteric inhibitor more potent than its parent open-chain peptide [Pro3]LR. In cytotoxicity studies on three human ovarian cancer cell lines, IGROV-1, A2780, and A2780/CP, peptide 5 and two other cPs, including 7, showed IC50 values comparable with those of the reference drug 5-fluorouracil, of the open-chain peptide [d-Gln4]LR, and of another seven prolyl derivatives of the lead peptide LR. These promising results indicate cP 7 as a possible lead compound to be chemically modified with the aim of improving both allosteric TS inhibitory activity and anticancer effectiveness.
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Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos Cíclicos / Timidilato Sintase / Inibidores Enzimáticos / Antineoplásicos Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Assunto principal: Peptídeos Cíclicos / Timidilato Sintase / Inibidores Enzimáticos / Antineoplásicos Limite: Humans Idioma: En Ano de publicação: 2019 Tipo de documento: Article