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Advantages and challenges of phenotypic screens: The identification of two novel antifungal geranylgeranyltransferase I inhibitors

Pries, Verena and Cotesta, Simona and Riedl, Ralph and Aust, Thomas and Schuierer, Sven and Tao, Jianshi and Filipuzzi, Ireos and Hoepfner, Dominic (2015) Advantages and challenges of phenotypic screens: The identification of two novel antifungal geranylgeranyltransferase I inhibitors. ACS Chemical Biology, 21 (3). pp. 306-315. ISSN 1087-05711552-454X

Abstract

Phenotypic screens are still the most effective starting points for compounds with desirable activities. To identify novel antifungal leads we have conducted a phenotypic screen in the yeast Saccharomyces cerevisiae and identified two different scaffolds with good growth inhibitory characteristics. Lack of broad spectrum antifungal activity against pathogenic fungi raised the question about the modulated target as required for directed chemical compound optimization. Chemogenomic profiling identified effects on geranylgeranyltransferase I (GGTase I), an enzyme that prenylates proteins involved in cell signaling like Cdc42p and Rho1p. Raising resistant mutants against both compounds confirmed the target hypothesis and allowed mapping of the compound binding site to the substrate binding pocket. Differential resistance conferring mutations and substrate competition for only one chemotype demonstrated a diverse binding mode for the two chemotypes. Exchange of the S.cerevisiae GGTase I complex by that of Candida albicans abolished growth inhibitory activity of both compounds thus confirming the identified target as well as the observed narrow antifungal spectrum. Reported lack of essentiality of this prenylation pathway in pathogenic species challenges the therapeutic value of these leads and demonstrates the importance of an integrated target identification platform following a phenotypic screen.

Item Type: Article
Date Deposited: 26 Apr 2016 23:45
Last Modified: 26 Apr 2016 23:45
URI: https://oak.novartis.com/id/eprint/26168

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