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 (2.0-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 [3H]-cholesterol and confirmed significant increases of [3H] 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. In addition, this compound proves that a small-molecule direct LCAT activator can achieve HDL-C elevation in monkey and reduction of atherosclerotic lesion area with enhanced HDL function in rodent.

• Authors: Masato Sasaki, Mina Delawary, Hidetaka Sakurai, Hideki Kobayashi, Naoki Nakao, Hiromi Tsuru, Yumiko Fukushima, Shoko Honzumi, Sachiko Moriyama, Naoya Wada, Toshio Kaneko, Keisuke Yamada, Naoki Terasaka, Kazuishi Kubota
• Journal: Arteriosclerosis, thrombosis, and vascular biology (Arterioscler Thromb Vasc Biol) Vol. 41 Issue 1 Pg. 360-376 (01 2021) ISSN: 1524-4636 [Electronic] United States
• PMID: 33086872 (Publication Type: Journal Article)

Chemical References

• Cholesterol, HDL
• Enzyme Activators
• Receptors, LDL
• LCAT protein, human
• Phosphatidylcholine-Sterol O-Acyltransferase

Topics

• Animals
• Atherosclerosis (enzymology, genetics, pathology, prevention & control)
• Cell Line
• Cholesterol, HDL (blood)
• Disease Models, Animal
• Enzyme Activation
• Enzyme Activators (pharmacology)
• Humans
• Macaca fascicularis
• Macrophages (drug effects, enzymology)
• Male
• Mice, Inbred C57BL
• Mice, Knockout
• Phosphatidylcholine-Sterol O-Acyltransferase (genetics, metabolism)
• Plaque, Atherosclerotic
• Receptors, LDL (deficiency, genetics)
• Species Specificity
• Up-Regulation