LY303366: A Noncompetitive Inhibitor of (1,3)-beta-D-Glucan Synthases from Candida albicans and Aspergillus fumigatus.

J.TANG, T.R.PARR JR., W.TURNER, M.DEBONO, L.LAGRANDEUR, F.BURKHARDT, M.RODRIQUEZ, M.ZWEIFEL, J.NISSEN, AND K.CLINGERMAN

Abstract: 

LY303366 a semisynthetic echinocandin B analog, is an antifungal agent active against C. albicans, A. fumigatus, Histoplasma capsulatum, and Pneumocystis carinii. This compound was found to be a noncompetitive inhibitor of both C. albicans and A. fumigatus (1,3)-beta-D-glucan synthases. Using in vitro glucan synthase reactions involving the polymerization of 14C UDP-glucose into TCA insoluble glucan, the IC50 for LY303366 was found to be 0.72 ± 0.26 ug/ml for C. albicans and 0. 17 ± 0.08 ug/ml for A. fumigatus. Using the method of Dixon, we determined the Ki app for LY303366 to be 0.7 ± 0.1 uM for C albicans and O.11 ± 0.0l uM for A.fumigatus. These LY303366 Ki's are 2-3 X lower than the Ki's of cilofungin for these enzymes. The structure activity relationship leading to LY303366 was guided in part by the glucan synthase inhibition assay. Minimum inhibitory concentrations of the lipopeptide series correlated with the C. albicans glucan synthase inhibition percentage at 1 ug/ml. The correlation coefficient for 195 examined compounds was 0.75.
1993

abstract No: 

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Full conference title: 

ICAAC 33rd, 1993
    • ICAAC 33rd