Yeast DNA topoisomerase II as a model molecular target for novel antifungal compounds

The project contains a proposal of complex interdisciplinary studies aimed at evaluation of molecular basis for the rational design of novel antifungals targeting fungal topoisomerase II (topoII). The high biochemical similarity between fungal and mammalian cells and the generation of resistance to already used chemotherapeutic agents make it desirable to search for new molecular targets. Topoisomerases belong to the family of enzymes involved in the processes related to DNA metabolism: transcription, replication, recombination and chromosome condensation. Although those enzymes are significant molecular targets in antibacterial and anticancer chemotherapy very little is known about the possibilities to target fungal topoII. Nevertheless, research indicates that fungal topoisomerases are crucial for the survival of some fungal strains, mammalian and fungal enzymes show diversity in terms of molecular structures and properties as well as differences in sensitivity to some inhibitors. Our preliminary results also strongly support the hypothesis of possible selective fungal topoII inhibition. The crucial goal of the project will be verified in consequence of the execution of three lines of research actions: a combined structure and docking based virtual screening, yeast topoisomerase II inhibition studies and final evaluation of biological properties of synthetized inhibitors. Completion of all planned studies should help to answer the question, whether compounds inhibiting fungal topoisomerase II, could be applied in the future for the treatment of disseminated mycoses.

Details

Project's acronym:: TopFUNG
Financial Program Name:: OPUS
Organization:: Narodowe Centrum Nauki (NCN) (National Science Centre)
Agreement:: UMO-2022/45/B/NZ6/01149 z dnia 2023-07-03
Realisation period:: 2023-07-04 - 2027-07-02
Project manager:: dr hab. inż. Iwona Gabriel
Realised in:: Department of Pharmaceutical Technology and Biochemistry
Project's value:: 1 610 400.00 PLN
Request type:: National Research Programmes
Domestic:: Domestic project
Verified by:: Gdańsk University of Technology

Papers associated with that project

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Year 2025

Anticancer drugs targeting topoisomerase II for antifungal treatment
Publication
- Scientific Reports - Year 2025
Fungal topoisomerase II (TopoII) has been identified as essential for viability. Thus, our research aimed to investigate the potential of fungal TopoII as a novel target for antifungal chemotherapy. We conducted studies on eleventh antitumor compounds targeting human topoisomerase II, either approved by the U.S. Food and Drug Administration (FDA) or currently under clinical trials to evaluate their potential for use in other therapeutic...

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Structural insights into fungal and human topoisomerase II with implications for in silico antifungal drug design
Publication
- Scientific Reports - Year 2025
Topoisomerases are essential enzymes regulating DNA supercoiling and disentanglement, critical for genomic integrity. While topoisomerase inhibitors are well-established in anticancer and antibacterial chemotherapy, their potential as antifungal agents remains underexplored or even not proofed. This study investigates structural distinctions between Saccharomyces cerevisiae topoisomerase II (ScTopoII) and human topoisomerase IIα...

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