The anti-atherogenic activity of beauveriolide derivative BVD327, a sterol O-Acyltransferase 2-Selective inhibitor, in apolipoprotein E knockout mice

Taichi Ohshiro, Satoshi Imuta, Ichiro Hijikuro, Hiroaki Yagyu, Takashi Takahashi, Takayuki Doi, Shun Ishibashi, Hiroshi Tomoda

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

The fungal 13-membered cyclodepsipeptides, beauveriolides I and III, were previously reported to be atheroprotective activity in mouse models via inhibiting sterol O-acyltransferase (SOAT) activity. A total of 149 beauveriolide derivatives (BVDs) synthesized combinatorially were evaluated in in silico absorption, distribution, metabolism and excretion (ADME) analysis and inhibitory activity toward the two SOAT isozymes, SOAT1 and SOAT2. Hence, only 11 BVDs exhibited SOAT2-selective inhibition. Among these, we chose BVD327, which had the highest ADME score, for further evaluation. BVD327 administration (50mg/kg/d, per os (p.o.)) significantly decreased atherosclerotic lesions in the aorta and heart (25.4±6.9 and 20.6±2.9%, respectively) in apolipoprotein E knockout (Apoe/) mice fed a cholesterol-enriched diet (0.2% cholesterol and 21% fat) for 12 weeks. These findings indicate that beauveriolide derivatives can be used as anti-atherosclerotic agents.

Original languageEnglish
Pages (from-to)951-958
Number of pages8
JournalBiological and Pharmaceutical Bulletin
Volume43
Issue number6
DOIs
Publication statusPublished - 2020

Keywords

  • Atherosclerosis
  • Beauveriolide
  • Inhibitor
  • Lipid metabolism
  • Sterol O-acyltransferase 2

ASJC Scopus subject areas

  • Pharmacology
  • Pharmaceutical Science

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