New fungal metabolite geranylgeranyltransferase inhibitors with antifungal activity.
Geranylgeranyltransferase I (GGTase I) catalyzes the post-translational transfer of lyophilic diterpenoid geranylgeranyl to the cysteine residue of proteins terminating with a CaaX motif such as Rho1p and Cdc42p. It has been shown that GGTase I activity is essential for viability of Saccharomyces cerevisiae and hence its inhibition is a potential antifungal target. From natural product screening, a number of azaphilones including one novel analog were isolated as broad-spectrum inhibitors of GGTase I. Isolation, structure elucidation, GGTase I inhibitory activities and antifungal activities of these compounds are described.
Singh, SB; Kelly, R; Guan, Z; Polishook, JD; Domrowski, AW; Collado, J; Gonzalez, A; Pelaez, F; Register, E; Kelly, TM; Bonfiglio, C; Williamson, JM
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