Authors:

Nathan Michael Henderson

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For the immunocompromised, pathogenic fungi are a serious concern causing over 1 million deaths annually from invasive infections [1]. Candida and Aspergillus species are responsible for over two-thirds of these deaths [1]. Within these fungal genera, the Cdc14 family of phosphatases has been identified as an attractive target for new drug design. Cdc14 is vital for fungal infection, as demonstrated through a mouse model in which loss of Cdc14 function rendered Candida albicans avirulent [2]. In addition, the Cdc14 active site is highly conserved and has a unique substrate specificity, making it a potentially effective and broad-range target. Moreover, it has been shown that Cdc14 orthologs in animals are not vital for growth or development [3]. The overall objective of my project was to pursue identification of small molecule Cdc14 inhibitors from chemical libraries as an initial step in the antifungal drug development process. All Cdc14 enzymes have a highly reactive cysteine catalytic residue in the active cite and therefore we screened for covalent inhibitors from chemical libraries. Aspergillus fumigatus Cdc14 was used as a model pathogen Cdc14 for this screen. And the activity of several pathogen Cdc14 enzymes were characterized to assess conservation of specificity and test if inhibitors of the screen would be broadly active. Then, various pathogen Cdc14 enzymes were expressed and purified to test suitability for X-ray crystallography analysis in complex with identified inhibitors. 16,606 compounds were screened, and 20 inhibitors were identified that exhibited at least 40% inhibition, with the highest displaying 85% inhibition. Subsequent experiments should now focus on further optimization of the broadest-acting inhibitors and animal trials to test their antifungal properties in living organisms. Keywords: Cdc14; Phosphatase; Drug Discovery; Covalent Inhibitor; Antifungal

Source:

Purdue University / 2024

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Co-authors:

Nathan Michael Henderson