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Optimization of peptides that target human thymidylate synthase to inhibit ovarian cancer cell growth

Michela Pelà1, Puneet Saxena, Rosaria Luciani

  • 1Department of Chemical and Pharmaceutical Sciences, University of Ferrara , via Fossato di Mortara 17-19, 44100 Ferrara, Italy.

Journal of Medicinal Chemistry
|January 24, 2014
PubMed

Insights

New peptide inhibitors show promise against ovarian cancer by targeting thymidylate synthase (TS). A d-glutamine modified peptide effectively inhibits cancer cell growth and overcomes drug resistance, offering a novel therapeutic strategy.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Oncology

Background:

  • Thymidylate synthase (TS) is a key target for ovarian cancer (OC) drugs like 5-fluorouracil (5-FU).
  • Drug resistance develops due to TS overexpression, limiting treatment efficacy.
  • Existing therapies often target the active site of TS, leading to resistance.

Purpose of the Study:

  • To develop novel peptide inhibitors targeting TS for ovarian cancer treatment.
  • To overcome drug resistance associated with current TS inhibitors.
  • To explore allosteric inhibition as an alternative strategy.

Main Methods:

  • Modification of a lead peptide (LR) to create 35 analogs.
  • In vitro testing of peptide efficacy against cisplatin-sensitive and -resistant OC cell lines.
  • Circular dichroism spectroscopy and molecular dynamics simulations to elucidate mechanisms.

Main Results:

  • A d-glutamine-modified peptide demonstrated superior inhibition of OC cell growth compared to LR and 5-FU.
  • The modified peptide induced a TS/DHFR expression pattern similar to the lead peptide.
  • Structural studies provided insights into the mechanism of enzyme inhibition.

Conclusions:

  • The d-glutamine-modified peptide represents a potent new lead for ovarian cancer therapy.
  • Allosteric stabilization of TS offers a viable strategy to overcome drug resistance.
  • Combined target inhibition and protein modulation approaches can yield effective OC drug leads.

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