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High-resolution chemogenomics identifies Litrafungin, a fungal-selective inhibitor of the lipid transfer protein Sec14p

Pries, Verena and Nöcker, Christina and Khan, Danish and Ashutosh, Tripathi and Perruccio, Francesca and Jonen, Philipp and Filipuzzi, Ireos and Thavam, Sasikala and Aust, Thomas and Riedl, Ralph and Ziegler, Slava and Schaaf, Gabriel and Bankaitis, Vytas and Waldmann, Herbert and Hoepfner, Dominic (2018) High-resolution chemogenomics identifies Litrafungin, a fungal-selective inhibitor of the lipid transfer protein Sec14p. Cell Chemical Biology, 25. pp. 1-12.

Abstract

Invasive fungal infections have high mortality rates ranging from 20% to 90%. Only three different compound classes are used in the clinic that often suffer from low bioavailability, toxicity and emerging drug resistance thus demonstrating an urgent need for novel antifungal agents. Here we report the identification of a pyridinecarboxamide scaffold series with antifungal properties. Using chemogenomic profiling we found a yeast strain with a heterozygous deletion of Sec14p, the major phosphatidylinositol transfer protein in Saccharomyces cerevisiae, to be hypersensitive. Direct testing of compounds in a lipid transfer assay with recombinant Sec14p corroborated the target hypothesis. Screening for compound resistance using a PCR mutagenesis approach identified resistance-conferring residues that localized to the lipid binding site of Sec14p. In silico docking approaches supported the binding of this scaffold into the lipid binding cavity and allowed to rationalize the observed structure-activity relationship. We thus propose the name Litrafungin for these fungal-selective lipid transfer inhibiting compounds.

Item Type: Article
Date Deposited: 19 Jan 2018 00:45
Last Modified: 19 Jan 2018 00:45
URI: https://oak.novartis.com/id/eprint/30587

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