Selectivity of Microbial Acyl-CoA : cholesterol Acyltransferase Inhibitors toward Isozymes

Abstract

The selectivity of microbial inhibitors of acyl-CoA : cholesterol acyltransferase (ACAT) toward the two isozymes, ACAT1 and ACAT2, was assessed in cell-based assays. Purpactin A (IC₅₀ values of ACAT1 vs. IC₅₀ values of ACAT2; 2.5 μM vs. 1.5 μM), terpendole C (10 μM vs. 10 μM), glisoprenin A (4.3 μM vs. 10 μM), spylidone (25 μM vs. 5.0 μM) and synthetic CL-283,546 (0.1 μM vs. 0.09 μM) inhibited ACAT1 and ACAT2 to similar extents. Beauveriolides I (0.6 μM vs. 20 μM) and III (0.9 μM vs. >20 μM) inhibited ACAT1 rather selectively, while pyripyropenes A (>80 μM vs. 0.07 μM), B (48 μM vs. 2.0 μM), C (32 μM vs. 0.36 μM) and D (38 μM vs. 1.5 μM) showed selective inhibition against ACAT2. In particular, pyripyropene A was found to be the most selective ACAT2 inhibitor with a selective index of more than 1,000.