The Anti-atherogenic Activity of Beauveriolide Derivative BVD327, a Sterol O-Acyltransferase 2-Selective Inhibitor, in Apolipoprotein E Knockout Mice
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 sili...
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| Veröffentlicht in: | Biological & pharmaceutical bulletin 2020/06/01, Vol.43(6), pp.951-958 |
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| creator | Ohshiro, Taichi Imuta, Satoshi Hijikuro, Ichiro Yagyu, Hiroaki Takahashi, Takashi Doi, Takayuki Ishibashi, Shun Tomoda, Hiroshi |
| description | 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. |
| doi_str_mv | 10.1248/bpb.b19-00913 |
| format | Article |
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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.</description><identifier>ISSN: 0918-6158</identifier><identifier>EISSN: 1347-5215</identifier><identifier>DOI: 10.1248/bpb.b19-00913</identifier><identifier>PMID: 32475917</identifier><language>eng</language><publisher>Japan: The Pharmaceutical Society of Japan</publisher><subject>Animal models ; Animals ; Aorta ; Aorta - drug effects ; Aorta - pathology ; Apolipoprotein E ; Apolipoproteins ; Arteriosclerosis ; Atherosclerosis ; Atherosclerosis - drug therapy ; Atherosclerosis - metabolism ; Atherosclerosis - pathology ; ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism ; beauveriolide ; Blood Proteins - metabolism ; Blood-Brain Barrier - metabolism ; Cholesterol ; Cytochrome P-450 CYP2C9 - metabolism ; Cytochrome P-450 CYP2D6 - metabolism ; ERG1 Potassium Channel - genetics ; Heart Valves - drug effects ; Heart Valves - pathology ; Humans ; inhibitor ; Intestinal Absorption ; Intestine, Small - drug effects ; Intestine, Small - metabolism ; Isoenzymes ; lipid metabolism ; Lipid Metabolism - drug effects ; Liver - drug effects ; Liver - metabolism ; Male ; Mice, Knockout, ApoE ; Rodents ; Sterol O-acyltransferase ; Sterol O-Acyltransferase - antagonists & inhibitors ; Sterol O-Acyltransferase - metabolism ; Sterol O-Acyltransferase 2 ; Sterols</subject><ispartof>Biological and Pharmaceutical Bulletin, 2020/06/01, Vol.43(6), pp.951-958</ispartof><rights>2020 The Pharmaceutical Society of Japan</rights><rights>Copyright Japan Science and Technology Agency 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c6173-8d1fb02a7f732c5c6a69334acc54fb6c6de5faae415fca5bec97b549cb885b343</citedby><cites>FETCH-LOGICAL-c6173-8d1fb02a7f732c5c6a69334acc54fb6c6de5faae415fca5bec97b549cb885b343</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,1877,27901,27902</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/32475917$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Ohshiro, Taichi</creatorcontrib><creatorcontrib>Imuta, Satoshi</creatorcontrib><creatorcontrib>Hijikuro, Ichiro</creatorcontrib><creatorcontrib>Yagyu, Hiroaki</creatorcontrib><creatorcontrib>Takahashi, Takashi</creatorcontrib><creatorcontrib>Doi, Takayuki</creatorcontrib><creatorcontrib>Ishibashi, Shun</creatorcontrib><creatorcontrib>Tomoda, Hiroshi</creatorcontrib><creatorcontrib>School of Medicine</creatorcontrib><creatorcontrib>cTokyo Chemical Industry CO</creatorcontrib><creatorcontrib>eFaculty of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>Jichi Medical University</creatorcontrib><creatorcontrib>School of Pharmacy</creatorcontrib><creatorcontrib>LTD</creatorcontrib><creatorcontrib>Nagoya University</creatorcontrib><creatorcontrib>fGraduate School of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>bMedicinal Research Laboratories</creatorcontrib><creatorcontrib>Department of Internal Medicine</creatorcontrib><creatorcontrib>Yokohama College of Pharmacy</creatorcontrib><creatorcontrib>dDivision of Endocrinology and Metabolism</creatorcontrib><creatorcontrib>aGraduate School of Pharmaceutical Sciences</creatorcontrib><creatorcontrib>Kitasato University</creatorcontrib><creatorcontrib>Tohoku University</creatorcontrib><creatorcontrib>Present address:Graduate School of Medicine</creatorcontrib><title>The Anti-atherogenic Activity of Beauveriolide Derivative BVD327, a Sterol O-Acyltransferase 2-Selective Inhibitor, in Apolipoprotein E Knockout Mice</title><title>Biological & pharmaceutical bulletin</title><addtitle>Biol Pharm Bull</addtitle><description>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. 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These findings indicate that beauveriolide derivatives can be used as anti-atherosclerotic agents.</description><subject>Animal models</subject><subject>Animals</subject><subject>Aorta</subject><subject>Aorta - drug effects</subject><subject>Aorta - pathology</subject><subject>Apolipoprotein E</subject><subject>Apolipoproteins</subject><subject>Arteriosclerosis</subject><subject>Atherosclerosis</subject><subject>Atherosclerosis - drug therapy</subject><subject>Atherosclerosis - metabolism</subject><subject>Atherosclerosis - pathology</subject><subject>ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism</subject><subject>beauveriolide</subject><subject>Blood Proteins - metabolism</subject><subject>Blood-Brain Barrier - metabolism</subject><subject>Cholesterol</subject><subject>Cytochrome P-450 CYP2C9 - metabolism</subject><subject>Cytochrome P-450 CYP2D6 - metabolism</subject><subject>ERG1 Potassium Channel - genetics</subject><subject>Heart Valves - drug effects</subject><subject>Heart Valves - 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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.</abstract><cop>Japan</cop><pub>The Pharmaceutical Society of Japan</pub><pmid>32475917</pmid><doi>10.1248/bpb.b19-00913</doi><tpages>8</tpages><oa>free_for_read</oa></addata></record> |
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| ispartof | Biological and Pharmaceutical Bulletin, 2020/06/01, Vol.43(6), pp.951-958 |
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| subjects | Animal models Animals Aorta Aorta - drug effects Aorta - pathology Apolipoprotein E Apolipoproteins Arteriosclerosis Atherosclerosis Atherosclerosis - drug therapy Atherosclerosis - metabolism Atherosclerosis - pathology ATP Binding Cassette Transporter, Subfamily B, Member 1 - metabolism beauveriolide Blood Proteins - metabolism Blood-Brain Barrier - metabolism Cholesterol Cytochrome P-450 CYP2C9 - metabolism Cytochrome P-450 CYP2D6 - metabolism ERG1 Potassium Channel - genetics Heart Valves - drug effects Heart Valves - pathology Humans inhibitor Intestinal Absorption Intestine, Small - drug effects Intestine, Small - metabolism Isoenzymes lipid metabolism Lipid Metabolism - drug effects Liver - drug effects Liver - metabolism Male Mice, Knockout, ApoE Rodents Sterol O-acyltransferase Sterol O-Acyltransferase - antagonists & inhibitors Sterol O-Acyltransferase - metabolism Sterol O-Acyltransferase 2 Sterols |
| title | The Anti-atherogenic Activity of Beauveriolide Derivative BVD327, a Sterol O-Acyltransferase 2-Selective Inhibitor, in Apolipoprotein E Knockout Mice |
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