Open AccessAntifungal Activity of Gepinacin Scaffold Glycosylphosphatidylinositol Anchor Biosynthesis Inhibitors with Improved Metabolic Stability
Author(s) -
Sean D. Liston,
Luke Whitesell,
Catherine A. McLellan,
Ralph Mazitschek,
Vidmantas Petraitis,
Rūta Petraitienė,
Povilas Kavaliauskas,
Thomas J. Walsh,
Leah E. Cowen
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.00899-20
Subject(s) - potency , antifungal , biosynthesis , pharmacokinetics , in vitro , metabolic stability , biochemistry , toxicity , pharmacology , solubility , biological activity , chemistry , biology , microbiology and biotechnology , enzyme , organic chemistry
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.