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Friday SN, Cheng DW, Zagler SG, et al. Design and testing of selective inactivators against an antifungal enzyme target. Drug Dev Res. 2021;doi: 10.1002/ddr.21875.
Friday, S. N., Cheng, D. W., Zagler, S. G., Zanella, B. S., Dietz, J. D., Calbat, C. N., Roach, L. T., Bagnal, C., Faile, I. S., Halkides, C. J., & Viola, R. E. (2021). Design and testing of selective inactivators against an antifungal enzyme target. Drug development research, . https://doi.org/10.1002/ddr.21875
Friday, Samantha N, et al. "Design and testing of selective inactivators against an antifungal enzyme target." Drug development research vol. (2021). doi: https://doi.org/10.1002/ddr.21875
Friday SN, Cheng DW, Zagler SG, Zanella BS, Dietz JD, Calbat CN, Roach LT, Bagnal C, Faile IS, Halkides CJ, Viola RE. Design and testing of selective inactivators against an antifungal enzyme target. Drug Dev Res. 2021 Sep 01; doi: 10.1002/ddr.21875. Epub 2021 Sep 01. PMID: 34469014.
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Drug Dev Res. 2021 Sep 01; doi: 10.1002/ddr.21875. Epub 2021 Sep 01.

Design and testing of selective inactivators against an antifungal enzyme target.

Drug development research

Samantha N Friday, Daniel W Cheng, Sebastian G Zagler, Brady S Zanella, Jordan D Dietz, Christopher N Calbat, Logan T Roach, Cindy Bagnal, Ian S Faile, Christopher J Halkides, Ronald E Viola

Affiliations

  1. Department of Chemistry and Biochemistry, University of Toledo, Toledo, Ohio, USA.
  2. Department of Chemistry and Biochemistry, University of North Carolina Wilmington, Wilmington, North Carolina, USA.

PMID: 34469014 DOI: 10.1002/ddr.21875

Abstract

Systemic infections from fungal organisms are becoming increasingly difficult to treat as drug resistance continues to emerge. To substantially expand the antifungal drug landscape new compounds must be identified and developed with novel modes of action against previously untested drug targets. Most drugs block the activity of their targets through reversible, noncovalent interactions. However, a significant number of drugs form irreversible, covalent bonds with their selected targets. While more challenging to develop, these irreversible inactivators offer some significant advantages as novel antifungal agents. Vinyl sulfones contain a potentially reactive functional group that could function as a selective enzyme inactivator, and members of this class of compounds are now being developed as inactivators against an antifungal drug target. The enzyme aspartate semialdehyde dehydrogenase (ASADH) catalyzes a key step in an essential microbial pathway and is essential for the survival of every microorganism examined. A series of vinyl sulfones have been designed, guided by molecular modeling and docking studies to enhance their affinity for fungal ASADHs. These newly synthesized compounds have been examined against this target enzyme from the pathogenic fungal organism Candida albicans. Vinyl sulfones containing complementary structural elements inhibit this enzyme with inhibition constants in the low-micromolar range. These inhibitors have also led to the rapid and irreversible inactivation of this enzyme, and show some initial selectivity when compared to the inactivation of a bacterial ASADH. The best inactivators will serve as lead compounds for the development of potent and selective antifungal agents.

© 2021 Wiley Periodicals LLC.

Keywords: antifungal agents; aspartate semialdehyde dehydrogenase; enzyme inactivators; enzyme inhibitors; vinyl sulfones

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