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

A1 Journal article (refereed)


Internal Authors/Editors


Publication Details

List of Authors: Cardinale, Guaitoli, Tondi, Luciani, Henrich, Salo-Ahen, Ferrari, Marverti, Guerrieri, Ligabue, Frassineti, Pozzi, Mangani, Fessas, Guerrini, Ponterini, Wade, Costi
Publisher: National Academy of Sciences
Publication year: 2011
Journal: Proceedings of the National Academy of Sciences
Journal acronym: Proc Natl Acad Sci U S A
Volume number: 108
Issue number: 34
Start page: E542
End page: 549
ISSN: 1091-6490
eISSN: 1091-6490


Abstract

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.

Last updated on 2019-11-11 at 03:16