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Intrinsic reactivity of Kdn glycosides and novel inhibitors of the Kdnases from pathogenic fungi

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Thesis type
(Thesis) Ph.D.
Date created
Author: Nejatie, Ali
Sialic acids are the focus of many studies due to their vital role in biological systems; the most common sialic acid being N-acetylneuraminic acid (Neu5Ac). 3-Deoxy-D-glycero-D-galacto-non-2-ulosonic acid (Kdn) is a member of the sialic acid family with its difference to Neu5Ac being at the C-5 position which is a hydroxyl group in Kdn. Research in Kdn and Kdn glycoconjugates (Kdnology) are not well understood as there is little known about its biological importance when compared to the other sialic acids. The fungal species Aspergillus fumigatus (Af) can use Kdn as a sole carbon source and has also shown to produce a Kdnase (AfK) which preferentially cleaves Kdn glycosides, rather than Neu5Ac glycosides. Af is the major causative agent in invasive aspergillosis (IA), a lethal disease affecting immunocompromised individuals. Current treatments for IA have limited success due either to high toxicity or the emergence of drug resistance and thus new therapeutics are needed. Aspergillus terreus (At) and Trichophyton rubrum (Tr) also produce a Kdnase and prefer Kdn substrates over Neu5Ac. At also causes IA in a lesser frequency but with a higher mortality rate. Tr is the major causative agent in skin disorders such as athletes' foot and jock itch and also problematic in immunocompromised patients. Kdnases are not present in human hosts thus make them prime targets for the development of new therapeutics. O-aryl Kdn glycosides are more reactive than their sialic acid analogues which is problematic when studying Kdnases. To circumvent its increased reactivity, we moved to use S-aryl Kdn thioglycosides. Although these thioglycosides were being hydrolyzed by AfK, they have too low a reactivity for our needs. We began to investigate why O-aryl Kdn glycosides were more reactive than their Neu5Ac analogues. We probed the C-5 substituent of these sialic acids by installing a 5-O-methyl group. This change provided us with some mechanistic insights into the non-enzymatic hydrolysis of Kdn aryl glycosides and allowed us to rationally design better probes for our needs. This led us to develop 2nd generation non-aryl self-immolative probes that solved the reactivity issues that have been problematic in studying Kdnases. Using these new probes, we screened over 27,000 bioactive compounds from two high-throughput screens and found potential Kdnase inhibitors, thus setting the groundwork for the development of novel therapeutics for the treatment of fungal diseases.
210 pages.
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Thesis advisor: Bennet, Andrew
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