Human thymidylate synthase is a homodimeric enzyme that playsa key role in DNA synthesis and is a target for several clinicallyimportant anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The “LR” peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer.

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase / Cardinale, Daniela; Guaitoli, Giambattista; Tondi, Donatella; Luciani, Rosaria; S., Henrich; O. M. H., Salo Ahen; Ferrari, Stefania; Marverti, Gaetano; Guerrieri, Davide; Ligabue, Alessio; Frassineti, Chiara; C., Pozzi; S., Mangani; D., Fessas; R., Guerrini; Ponterini, Glauco; R. C., Wade; Costi, Maria Paola. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 108:34(2011), pp. E542-E549. [10.1073/pnas.1104829108]

Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase

CARDINALE, Daniela;GUAITOLI, GIAMBATTISTA;TONDI, Donatella;LUCIANI, Rosaria;FERRARI, Stefania;MARVERTI, Gaetano;GUERRIERI, Davide;LIGABUE, Alessio;FRASSINETI, Chiara;PONTERINI, Glauco;COSTI, Maria Paola
2011

Abstract

Human thymidylate synthase is a homodimeric enzyme that playsa key role in DNA synthesis and is a target for several clinicallyimportant anticancer drugs that bind to its active site. We have designed peptides to specifically target its dimer interface. Here we show through X-ray diffraction, spectroscopic, kinetic, and calorimetric evidence that the peptides do indeed bind at the interface of the dimeric protein and stabilize its di-inactive form. The “LR” peptide binds at a previously unknown binding site and shows a previously undescribed mechanism for the allosteric inhibition of a homodimeric enzyme. It inhibits the intracellular enzyme in ovarian cancer cells and reduces cellular growth at low micromolar concentrations in both cisplatin-sensitive and -resistant cells without causing protein overexpression. This peptide demonstrates the potential of allosteric inhibition of hTS for overcoming platinum drug resistance in ovarian cancer.
2011
30-giu-2011
108
34
E542
E549
Protein–protein interface-binding peptides inhibit the cancer therapy target human thymidylate synthase / Cardinale, Daniela; Guaitoli, Giambattista; Tondi, Donatella; Luciani, Rosaria; S., Henrich; O. M. H., Salo Ahen; Ferrari, Stefania; Marverti, Gaetano; Guerrieri, Davide; Ligabue, Alessio; Frassineti, Chiara; C., Pozzi; S., Mangani; D., Fessas; R., Guerrini; Ponterini, Glauco; R. C., Wade; Costi, Maria Paola. - In: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA. - ISSN 0027-8424. - STAMPA. - 108:34(2011), pp. E542-E549. [10.1073/pnas.1104829108]
Cardinale, Daniela; Guaitoli, Giambattista; Tondi, Donatella; Luciani, Rosaria; S., Henrich; O. M. H., Salo Ahen; Ferrari, Stefania; Marverti, Gaetano...espandi
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/662646
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