The Anti-atherogenic Activity of Beauveriolide Derivative BVD327, a Sterol O-Acyltransferase 2-Selective Inhibitor, in Apolipoprotein E Knockout Mice

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  • Ohshiro Taichi
    Graduate School of Pharmaceutical Sciences, Kitasato University Medicinal Research Laboratories, School of Pharmacy, Kitasato University
  • Imuta Satoshi
    Tokyo Chemical Industry CO., LTD.
  • Hijikuro Ichiro
    Tokyo Chemical Industry CO., LTD.
  • Yagyu Hiroaki
    Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University
  • Takahashi Takashi
    Faculty of Pharmaceutical Sciences, Yokohama College of Pharmacy
  • Doi Takayuki
    Graduate School of Pharmaceutical Sciences, Tohoku University
  • Ishibashi Shun
    Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University
  • Tomoda Hiroshi
    Graduate School of Pharmaceutical Sciences, Kitasato University Medicinal Research Laboratories, School of Pharmacy, Kitasato University

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  • The Anti-atherogenic Activity of Beauveriolide Derivative BVD327, a Sterol <i>O</i>-Acyltransferase 2-Selective Inhibitor, in Apolipoprotein E Knockout Mice

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<p>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 (50 mg/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.</p>

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