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

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

  • Biol Pharm Bull. 2020;43(6):951-958. doi: 10.1248/bpb.b19-00913.
Taichi Ohshiro 1 2,  Satoshi Imuta 3,  Ichiro Hijikuro 3,  Hiroaki Yagyu 4,  Takashi Takahashi 5,  Takayuki Doi 6,  Shun Ishibashi 4,  Hiroshi Tomoda 1 2
Affiliations

Affiliations

  • 1 Graduate School of Pharmaceutical Sciences, Kitasato University.
  • 2 Medicinal Research Laboratories, School of Pharmacy, Kitasato University.
  • 3 Tokyo Chemical Industry CO., LTD.
  • 4 Division of Endocrinology and Metabolism, Department of Internal Medicine, School of Medicine, Jichi Medical University.
  • 5 Faculty of Pharmaceutical Sciences, Yokohama College of Pharmacy.
  • 6 Graduate School of Pharmaceutical Sciences, Tohoku University.
PMID: 32475917 DOI: 10.1248/bpb.b19-00913
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 (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.

Keywords

atherosclerosis; beauveriolide; inhibitor; lipid metabolism; sterol O-acyltransferase 2.

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