- Tytuł:
- Thiopurine derivative-induced Fpg/Nei DNA glycosylase inhibition : structural, dynamic and functional insights
- Autorzy:
-
Garnier, Norbert
Tber, Zahira
Bourg, Stéphane
Agrofoglio, Luigi
Castang, Bertrand
Cros, Julien
Roy, Vincent
Guerin, Martine
Goffinont, Stéphane
Rieux, Charlotte
Biela, Artur
Gaudon, Virginie
Aucagne, Vincent
Coste, Franck - Opis:
- DNA glycosylases are emerging as relevant pharmacological targets in inflammation, cancer and neurodegenerative diseases. Consequently, the search for inhibitors of these enzymes has become a very active research field. As a continuation of previous work that showed that 2-thioxanthine (2TX) is an irreversible inhibitor of zinc finger (ZnF)-containing Fpg/Nei DNA glycosylases, we designed and synthesized a mini-library of 2TX-derivatives (TXn) and evaluated their ability to inhibit Fpg/Nei enzymes. Among forty compounds, four TXn were better inhibitors than 2TX for Fpg. Unexpectedly, but very interestingly, two dithiolated derivatives more selectively and e ciently inhibit the zincless finger (ZnLF)-containing enzymes (human and mimivirus Neil1 DNA glycosylases hNeil1 and MvNei1, respectively). By combining chemistry, biochemistry, mass spectrometry, blind and flexible docking and X-ray structure analysis, we localized new TXn binding sites on Fpg/Nei enzymes. This endeavor allowed us to decipher at the atomic level the mode of action for the best TXn inhibitors on the ZnF-containing enzymes. We discovered an original inhibition mechanism for the ZnLF-containing Fpg/Nei DNA glycosylases by disulfide cyclic trimeric forms of dithiopurines. This work paves the way for the design and synthesis of a new structural class of inhibitors for selective pharmacological targeting of hNeil1 in cancer and neurodegenerative diseases.
- Dostawca treści:
- Repozytorium Uniwersytetu Jagiellońskiego
Artykuł