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New peptides to fight ovarian cancer drug resistance
01 August 2011
Heidelberg Institute for Theoretical Studies
Italian and German scientists have designed peptides to target the protein-protein interface of a key enzyme in DNA synthesis crucial for cancer growth. The peptides act by a novel inhibitory mechanism and curb cancer cell growth in drug resistant ovarian cancer cells. The interdisciplinary research project was led by the University of Modena and Reggio Emilia (UNIMORE) and the Heidelberg Institute for Theoretical Studies (HITS).
Worldwide, over 200,000 women are diagnosed with ovarian cancer every year, with higher incidence in developed countries where it is the fifth leading cause of cancer-related deaths in women. Ovarian cancer has a high mortality rate due to frequent late diagnosis and the rapid development of drug resistance. Several clinically important anti-cancer drugs that are widely used in chemotherapy inhibit the enzyme, thymidylate synthase, which plays a key role in DNA synthesis. However, the use of these drugs is associated with drug resistance and new compounds with different inhibitory mechanisms are required to combat resistance.
Scientists from Italy and Germany have designed octapeptides that specifically target the protein-protein interface of thymidylate synthase. Thymidylate synthase is composed of two identical polypeptide chains, i.e. it is a homodimer. The peptides stabilize the inactive form of the enzyme, show a novel mechanism of inhibition for homodimeric enzymes, and inhibit cell growth in drug sensitive and resistant cancer cell lines.
The interdisciplinary collaboration between scientists in Italy and Germany, led by Maria Paola Costi and Glauco Ponterini at the University of Modena and Reggio Emilia, Stefano Mangani at the University of Siena (UNISI) and Rebecca Wade at Heidelberg Institute for Theoretical Studies (HITS), was part of the LIGHTS project (LIGands to interfere with human TS). The project was supported by the Sixth Framework Programme (FP6), an EU scheme to fund and promote European research and technological development.
The researchers have discovered several peptides that inhibit thymidylate synthase by modulating protein-protein interactions. Maria Paola Costi explains: “These peptides have sequences from the protein-protein interface of the enzyme and inhibit it by binding to a previously unknown allosteric binding site - that is, a site other than the protein's active site - at the protein-protein interface.” By a combination of experimental and computational approaches, it was shown that their inhibitory mechanism involving stabilization of an inactive form of the catalytic protein differs from those of protein-protein interface inhibitors reported to date.
Unlike the existing drugs targeting thymidylate synthase, these peptides inhibit intra-cellular thymidylate synthase and cell growth without leading to increased levels of thymidylate synthase protein when administered to ovarian cancer cells. “This observation indicates the potential value of these peptides in overcoming drug resistance problems, although the cellular effects remain to be fully explored,” says Rebecca Wade. Further steps will require optimization of the compounds discovered and detailed analysis of their cellular mechanism of action. The concepts revealed by this work can be expected to provide new avenues for the development of drugs for combating diseases such as ovarian cancer.
Structure of human thymidylate synthase with an inhibitory peptide bound at its dimer interface determined by x-ray crystallography. The protein is shown with a cartoon representation of its secondary structure colored according to sequence and the peptide is colored by atom-type with its electron density contoured in blue (Cardinale et al).,