Identification and semisynthesis of(-)-anisomelic acid as oral agent against SARS-CoV-2 in mice

作     者：Hai-Xin Yu Nan Zheng Chi-Tai Yeh Chien-Ming Lee Qi Zhang Wen-Lv Zheng Qing Chang Yuan-He Li Yu-Jun Li Gui-Zhen Wu Jun-Min Quan Lin-Qi Zhang Yew-Min Tzeng Zhen Yang Hai-Xin Yu;Nan Zheng;Chi-Tai Yeh;Chien-Ming Lee;Qi Zhang;Wen-Lv Zheng;Qing Chang;Yuan-He Li;Yu-Jun Li;Gui-Zhen Wu;Jun-Min Quan;Lin-Qi Zhang;Yew-Min Tzeng;Zhen Yang

作者机构：Laboratory of Chemical Genomics School of Chemical Biology and Biotechnology Peking University Shenzhen Graduate School Department of Medicinal Research and EducationTaipei Medical University-Shuang Ho Hospital Department of Applied Science Taitung University Center for Global Health and Infectious DiseasesComprehensive AIDS Research Center and Beijing Advanced Innovation Center for Structural Biology School of Medicine Tsinghua University Lanzhou Institute of Separation Science State Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National Laboratory for Molecular Science(BNLMS) College of Chemistry and Molecular EngineeringPeking University Shenzhen Bay Laboratory NHC Key Laboratory of BiosafetyNational Institute for Viral Disease Control and Prevention Chinese Center for Disease Control and Prevention Department of Applied ChemistryChaoyang University of Technology 

出 版 物：《National Science Review》 (国家科学评论(英文版))

年 卷 期：2022年第9卷第11期

页      面：29-36页

核心收录：

学科分类：0710[理学-生物学] 1006[医学-中西医结合] 1002[医学-临床医学] 1001[医学-基础医学(可授医学、理学学位)] 0703[理学-化学] 10[医学] 100602[医学-中西医结合临床] 

基　　金：supported by the National Natural Science Foundation of China (21772004, 21871012, 21933004, 21632002,21521003 and 22077009) the Ministry of Science and Technology of China (2022YFC0868400) 

主　　题：identification enantioselective semisynthesis (−)-anisomelic acid oral agent anti-SARS-CoV-2 

摘      要：(-)-Anisomelic acid, isolated from Anisomeles indica(L.) Kuntze(Labiatae) leaves, is a macrocyclic cembranolide with a trans-fused α-methylene-γ-lactone motif. Anisomelic acid effectively inhibits SARS-Co V-2 replication and viral-induced cytopathic effects with an EC50 of 1.1 and 4.3 μM, respectively.Challenge studies of SARS-CoV-2-infected K18-hACE2 mice showed that oral administration of anisomelic acid and subcutaneous dosing of remdesivir can both reduce the viral titers in the lung tissue at the same level. To facilitate drug discovery, we used a semisynthetic approach to shorten the project timelines. The enantioselective semisynthesis of anisomelic acid from the naturally enriched and commercially available starting material(+)-costunolide was achieved in five steps with a 27% overall yield.The developed chemistry provides opportunities for developing anisomelic-acid-based novel ligands for selectively targeting proteins involved in viral infections.