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
Sheo B
SB
Merck Research laboratories, P.O. Box 2000, Rahway, NJ 07065, USA. sheo_singh@merck.com
Kelly
Rosemarie
R
Guan
Ziqiang
Z
Polishook
Jon D
JD
Domrowski
Anne W
AW
Collado
Javier
J
Gonzalez
Antonio
A
Pelaez
Fernando
F
Register
Elizabeth
E
Kelly
Theresa M
TM
Bonfiglio
Cynthia
C
Williamson
Joanne M
JM
D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000935:Antifungal Agents / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D001578:Benzopyrans / Q000494:pharmacology*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000494:pharmacology*; D010860:Pigments, Biological / Q000494:pharmacology*; D012441:Saccharomyces cerevisiae / Q000201:enzymology*; D029701:Saccharomyces cerevisiae Proteins / Q000037:antagonists & inhibitors
D000935:Antifungal Agents; D001578:Benzopyrans; D004791:Enzyme Inhibitors; D010860:Pigments, Biological; D029701:Saccharomyces cerevisiae Proteins; C494154:azaphilone; D019883:Alkyl and Aryl Transferases; C083291:geranylgeranyltransferase type-I