Squalestatin 1, a potent inhibitor of squalene synthase, which lowers serum cholesterol in vivo.
Baxter A,
Fitzgerald BJ,
Hutson JL,
McCarthy AD,
Motteram JM,
Ross BC,
Sapra M,
Snowden MA,
Watson NS,
Williams RJ, et al.
Glaxo Group Research Ltd., Greenford, Middlesex, United Kingdom.
Squalestatin 1 is a member of a novel family of fermentation products isolated from a previously unknown Phoma species (Coelomycetes). Squalestatin 1 is a potent, selective inhibitor of squalene synthase, a key enzyme in cholesterol biosynthesis; in vitro, 50% inhibition of enzyme activity is observed at a concentration of 12 +/- 5 nM (range of 4-22 nM). Squalestatin 1 inhibits cholesterol biosynthesis from [14C]acetate by isolated rat hepatocytes (50% inhibition at 39 nM) and by rat liver in vivo. In marmosets, a species with a lipoprotein profile similar to that of man, squalestatin 1 lowers serum cholesterol by up to 75%. This compound will allow further investigation of the control of the sterol biosynthesis pathway and could also lead to the development of new therapies for elevated serum cholesterol.
PMID: 1601846 [PubMed - indexed for MEDLINE]