期刊
CHEMISTRY-A EUROPEAN JOURNAL
卷 24, 期 32, 页码 8103-8113出版社
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201800729
关键词
antimalarial agents; dendrimers; drug design; drug discovery; proteomics
资金
- Deutsche Forschungsgemeinschaft (DFG) [TS 87/16-3]
- Emerging Fields Initiative (EFI) Chemistry in Live Cells - Friedrich-Alexander-Universitat Erlangen-Nurnberg
- Deutsche Forschungsgemeinschaft [MA 1289/7-3, MA 1289/11-1]
- discovery platform and informatics group at EDyP
- Proteomics French Infrastructure [ANR-10-INBS-08-01]
- Labex GRAL [ANR-10-LABX-49-01]
- Interdisciplinary Center for Molecular Materials (ICMM)
- Graduate School Molecular Science (GSMS)
Generation of dimers, trimers and dendrimers of bioactive compounds is an approach that has recently been developed for the discovery of new potent drug candidates. Herein, we present the synthesis of new artemisinin-derived dimers and dendrimers and investigate their action against malaria parasite Plasmodium falciparum 3D7 strain and human cytomegalovirus (HCMV). Dimer 7 was the most active compound (EC50 1.4 nm) in terms of antimalarial efficacy and was even more effective than the standard drugs dihydroartemisinin (EC50 2.4 nm), artesunic acid (EC50 8.9 nm) and chloroquine (EC50 9.8 nm). Trimer 4 stood out as the most active agent against HCMV in vitro replication and exerted an EC50 value of 0.026 mu m, representing an even higher activity than the two reference drugs ganciclovir (EC50 2.60 mu m) and artesunic acid (EC50 5.41 mu m). In addition, artemisinin-derived dimer 13 and trimer 15 were for the first time both immobilized on TOYOPEARL AF-Amino-650M beads and used for mass spectrometry-based target identification experiments using total lysates of HCMV-infected primary human fibroblasts. Two major groups of novel target candidates, namely cytoskeletal and mitochondrial proteins were obtained. Two putatively compound-binding viral proteins, namely major capsid protein (MCP) and envelope glycoprotein pUL132, which are both essential for HCMV replication, were identified.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据