Inhibition of cholesteryl ester transfer protein by fungal metabolites, L681,512.

The cholesteryl ester transfer protein (CETP) promotes exchange and transfer of neutral lipids such as cholesteryl ester (CE) and triacylglycerol (TG) between plasma lipoproteins. Evidence is accumulating for involvement of CETP in atherosclerosis1'2). Therefore, CETP is expected as a novel target of inhibition for anti-atherosclerotic agents. In the course of our screening for CETP inhibitors of microbial origin3~7), four active compounds were isolated from the culture broth of a fungal Fusarium sp. FO-6651. Based on its physico-chemical properties and NMRdata, they were identified with L681,512 compounds8'9), which were previously reported as elastase inhibitors. In this paper, the fermentation, isolation and in vitro CETP inhibitory activity of L681,512 compounds are described. Furthermore, we show that L681,512-1 proves effective in the ex vivo assay using human CETP and apo A-I