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

Cardinale, Guaitoli, Tondi, Luciani, Henrich, Outi Salo-Ahen, Ferrari, Marverti, Guerrieri, Ligabue, Frassineti, Pozzi, Mangani, Fessas, Guerrini, Ponterini, Wade, Costi

    Research output: Contribution to journalArticleScientificpeer-review

    72 Citations (Scopus)


    Human thymidylate synthase is a homodimeric enzyme that plays a key role in DNA synthesis and is a target for several clinically important 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.
    Original languageUndefined/Unknown
    Pages (from-to)E542–549
    JournalProceedings of the National Academy of Sciences
    Issue number34
    Publication statusPublished - 2011
    MoE publication typeA1 Journal article-refereed

    Cite this