Novel LCAT (Lecithin:Cholesterol Acyltransferase) Activator DS-8190a Prevents the Progression of Plaque Accumulation in Atherosclerosis Models

Abstract

Objective: Enhancement of LCAT (lecithin:cholesterol acyltransferase) activity has possibility to be beneficial for atherosclerosis. To evaluate this concept, we characterized our novel, orally administered, small-molecule LCAT activator DS-8190a, which was created from high-throughput screening and subsequent derivatization. We also focused on its mechanism of LCAT activation and the therapeutic activity with improvement of HDL (high-density lipoprotein) functionality. Approach and Results: DS-8190a activated human and cynomolgus monkey but not mouse LCAT enzymes in vitro. DS-8190a was orally administered to cynomolgus monkeys and dose dependently increased LCAT activity (ca. 2.1-fold in 3 mg/kg group on day 7), resulting in HDL cholesterol elevation without drastic changes of non-HDL cholesterol. Atheroprotective effects were then evaluated using Ldl-r KO × hLcat Tg mice fed a Western diet for 8 weeks. DS-8190a treatment achieved significant reduction of atherosclerotic lesion area (48.3% reduction in 10 mg/kg treatment group). Furthermore, we conducted reverse cholesterol transport study using Ldl-r KO × hLcat Tg mice intraperitoneally injected with J774A.1 cells loaded with [ 3 H]-cholesterol and confirmed significant increases of [ 3 H] count in plasma (1.4-fold) and feces (1.4-fold on day 2 and 1.5-fold on day3) in the DS-8190a–treated group. With regard to the molecular mechanism involved, direct binding of DS-8190a to human LCAT protein was confirmed by 2 different approaches: affinity purification by DS-8190a–immobilized beads and thermal shift assay. In addition, the candidate binding site of DS-8190a in human LCAT protein was identified by photoaffinity labeling. Conclusions: This study demonstrates the potential of DS-8190a as a novel therapeutic for atherosclerosis. This is also the first report describing that a small-molecule direct LCAT activator achieved HDL cholesterol elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.

Effects of Elaidic Acid on HDL Cholesterol Uptake Capacity

“…CUC was significantly enhanced in the presence of rhLCAT. Recently, therapeutic concepts for coronary heart disease and atherosclerosis using recombinant LCAT protein or an LCAT activator have been proposed, and dose-dependent increases in HDL-C along with the enhancement of cholesterol efflux or in vivo reverse cholesterol transport (RCT) have been demonstrated [ 30 , 43 ]. Considering the enhancement of CUC in the presence of rhLCAT, as shown in this study, CUC may change in response to these molecules, in a manner similar to cholesterol efflux.…”

Regulation of cholesterol homeostasis in health and diseases: from mechanisms to targeted therapeutics

“…Oral administration of DS-8190A also stimulated RCT process in primate cynomolgus monkeys. 363 These studies suggest that LCAT activation may help to reduce residual risk of ASCVD.…”

Apolipoprotein A1-Related Proteins and Reverse Cholesterol Transport in Antiatherosclerosis Therapy: Recent Progress and Future Perspectives

“…It has been found that compound A (3-(5-(ethylthio)-1,3,4-thiadiazol-2-ylthio)pyrazine-2-carbonitrile) covalently binds to Cys31 at the active site of LCAT, increases the levels of CE and HDL-C in the plasma of mice and hamsters, and develops sulfhydryl reactive β -lactam as a new type of LCAT activator [ 75 , 76 ]. Recent studies have found that a new oral small molecule LCAT activator, DS-8190, increased HDL-C and reduced the area of atherosclerotic lesions by directly binding to human LCAT protein [ 77 ].…”