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Bacterial amidohydrolases and modified 5-fluorocytidine compounds: Novel enzyme-prodrug pairs

Viktorija Preitakaitė1, Povilas Barasa2, Agota Aučynaitė1

  • 1Department of Molecular Microbiology and Biotechnology, Institute of Biochemistry, Life Sciences Center, Vilnius University, Vilnius, Lithuania.

Plos One
|November 30, 2023
PubMed

Insights

Bacterial amidohydrolases YqfB and D8_RL can activate novel prodrugs. This enzyme-prodrug system shows promise for gene-directed enzyme prodrug therapy, reducing cancer cell viability.

Area of Science:

  • Biochemistry
  • Molecular Biology
  • Cancer Therapeutics

Background:

  • Gene-directed enzyme prodrug therapy (GDEPT) is an innovative cancer treatment.
  • Current GDEPT approaches are limited by enzyme availability and prodrug design.
  • Novel enzyme-prodrug systems are needed to enhance therapeutic efficacy.

Purpose of the Study:

  • To evaluate bacterial amidohydrolases YqfB and D8_RL for prodrug activation.
  • To assess the efficacy of novel cytidine-based prodrugs in cancer cells.
  • To determine the potential of these enzymes as GDEPT agents.

Main Methods:

  • Established cancer cell lines stably expressing YqfB or D8_RL.
  • Synthesized and selected N4-acylated cytidine derivatives as prodrugs.
  • Assessed cancer cell viability upon prodrug exposure.

Main Results:

  • Bacterial amidohydrolases YqfB and D8_RL successfully activated novel prodrugs.
  • Significant reduction in HCT116 colon cancer cell viability was observed.
  • Demonstrated the cytotoxic effect of the activated prodrugs in engineered cells.

Conclusions:

  • Bacterial YqfB and D8_RL amidohydrolases are effective in activating novel cytidine-based prodrugs.
  • This enzyme-prodrug combination shows potential for GDEPT applications.
  • The system offers a promising new strategy for targeted cancer therapy.

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