**9. Conclusions**

DNA glycosylases, as enzymes that initiate base excision repair, represent an attractive pharmacological target. Their structures reveal mechanism-based features, such as deep pockets for substrate base binding, indicating potential druggability, and several successful attempts of library screening produced tantalizing leads that can be explored further to develop drugs for cancer and infectious diseases. Moreover, recent findings implicate DNA glycosylases not only in genome protection but also in regulatory pathways and suggest that they can be targeted in some inflammatory and neurodegenerative processes. A number of rapid and sensitive assays for screening DNA glycosylase activities were developed in the past few years, which should facilitate the search for their inhibitors.

The most important factor that complicates the targeting of DNA glycosylases in the now well-established framework of synthetic lethality, e.g., in cancer therapy, is their dual function in cell killing. On one hand, glycosylases initiate the repair of genotoxic adducts and, in theory, should potentiate their action. On the other hand, there are many cases in which the main lethal lesions are not adducts per se but intermediates of their repair, such as AP sites or DNA breaks. Such intermediates usually accumulate if the activity of downstream BER enzymes are insufficient to process the inflicted amount of genomic lesions in full. In these situations, DNA glycosylase inhibition would protect rather than sensitize cells to genome damage. Optimally, DNA glycosylases should be targeted in some form of precision therapy, based on the general model of toxicity of various adducts and the specific knowledge of adduct spectra and downstream BER capacity in the affected cells.

Outside of the cancer field, DNA glycosylase inhibition is most likely to find its soonest clinical application in antiviral therapy, since two important groups of human pathogens, poxviruses and herpesviruses, possess their own uracil-DNA glycosylases, a validated target required for replication in host cells, and several promising drug leads are available. Inhibition of OGG1 to prevent somatic trinucleotide repeat expansion in Huntington's disease also has high priority due to the extreme morbidity and mortality of the condition and the lack of other drugs, although lead compounds capable of brain delivery have not been reported so far. The inflammation-modulating action of OGG1 inhibitors, albeit attracting considerable attention, would still require much research and mechanistic insights to produce drugs comparable with more traditional anti-inflammatory agents. Even if more basic research is required to validate DNA glycosylases as targets for antibacterial combination therapy, yet the payoff in this area may be the largest one. The prospects of bringing DNA glycosylases into the circle of drug targets ultimately depend on our understanding of their action in DNA repair and connection with other cellular pathways.

**Author Contributions:** Conceptualization, D.O.Z. writing—original draft preparation, G.V.M., A.V.E., E.A.D., and D.O.Z.; writing—review and editing, D.O.Z.; visualization, D.O.Z.; supervision, D.O.Z.; project administration, D.O.Z.; funding acquisition, A.V.E. and D.O.Z. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research was funded by the Russian Science Foundation, grant 19-74-00068. Partial salary support from the Russian Ministry of Science and Higher Education (State funded budget project AAAA-A17-117020210023-1) is acknowledged. Open Access fees were paid by an intramural program of SB RAS Institute of Chemical Biology and Fundamental Medicine.

**Conflicts of Interest:** The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
