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Antifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability. 2020
Sean D Liston, and
Luke Whitesell, and
Catherine A McLellan, and
Ralph Mazitschek, and
Vidmantas Petraitis, and
Ruta Petraitiene, and
Povilas Kavaliauskas, and
Thomas J Walsh, and
Leah E Cowen
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
The glycosylphosphatidylinositol anchor biosynthesis inhibitor gepinacin demonstrates broad-spectrum antifungal activity and negligible mammalian toxicity in culture but is metabolically labile. The stability and bioactivity of 39 analogs were tested in vitro to identify LCUT-8, a stabilized lead with increased potency and promising single-dose pharmacokinetics. Unfortunately, no antifungal activity was seen at the maximum dosing achievable in a neutropenic rabbit model. Nevertheless, structure-activity relationships identified here suggest strategies to further improve compound potency, solubility, and stability.
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