iScience (Apr 2021)
Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment
- Hirofumi Ohashi,
- Koichi Watashi,
- Wakana Saso,
- Kaho Shionoya,
- Shoya Iwanami,
- Takatsugu Hirokawa,
- Tsuyoshi Shirai,
- Shigehiko Kanaya,
- Yusuke Ito,
- Kwang Su Kim,
- Takao Nomura,
- Tateki Suzuki,
- Kazane Nishioka,
- Shuji Ando,
- Keisuke Ejima,
- Yoshiki Koizumi,
- Tomohiro Tanaka,
- Shin Aoki,
- Kouji Kuramochi,
- Tadaki Suzuki,
- Takao Hashiguchi,
- Katsumi Maenaka,
- Tetsuro Matano,
- Masamichi Muramatsu,
- Masayuki Saijo,
- Kazuyuki Aihara,
- Shingo Iwami,
- Makoto Takeda,
- Jane A. McKeating,
- Takaji Wakita
Affiliations
- Hirofumi Ohashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
- Koichi Watashi
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan; Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan; MIRAI, JST, Saitama 332-0012, Japan; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Corresponding author
- Wakana Saso
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Kaho Shionoya
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
- Shoya Iwanami
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
- Takatsugu Hirokawa
- Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan; Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan; Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan
- Tsuyoshi Shirai
- Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan
- Shigehiko Kanaya
- Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 630-0192, Japan
- Yusuke Ito
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
- Kwang Su Kim
- Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
- Takao Nomura
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
- Tateki Suzuki
- Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan
- Kazane Nishioka
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
- Shuji Ando
- Department of Virology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Keisuke Ejima
- Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, IN 47405, USA
- Yoshiki Koizumi
- National Center for Global Health and Medicine, Tokyo 162-8655, Japan
- Tomohiro Tanaka
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
- Shin Aoki
- Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan; Research Institute for Science and Technology, Tokyo University of Science, Noda 278-8510, Japan
- Kouji Kuramochi
- Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
- Tadaki Suzuki
- Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Takao Hashiguchi
- Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan
- Katsumi Maenaka
- Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan; Global Station for Biosurfaces and Drug Discovery, Center for Life Innovation, Hokkaido University, Sapporo 060-0812, Japan
- Tetsuro Matano
- The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan; AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Masamichi Muramatsu
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Masayuki Saijo
- Department of Virology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Kazuyuki Aihara
- International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-8654, Japan
- Shingo Iwami
- MIRAI, JST, Saitama 332-0012, Japan; Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan; Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan; NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan; Science Groove Inc., Fukuoka 810-0041, Japan
- Makoto Takeda
- Department of Virology III, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
- Jane A. McKeating
- Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
- Takaji Wakita
- Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
- Journal volume & issue
-
Vol. 24,
no. 4
p. 102367
Abstract
Summary: Antiviral treatments targeting the coronavirus disease 2019 are urgently required. We screened a panel of already approved drugs in a cell culture model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and identified two new agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine in VeroE6/TMPRSS2 cells: the anti-inflammatory drug cepharanthine and human immunodeficiency virus protease inhibitor nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry through the blocking of viral binding to target cells, while nelfinavir suppressed viral replication partly by protease inhibition. Consistent with their different modes of action, synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation was highlighted. Mathematical modeling in vitro antiviral activity coupled with the calculated total drug concentrations in the lung predicts that nelfinavir will shorten the period until viral clearance by 4.9 days and the combining cepharanthine/nelfinavir enhanced their predicted efficacy. These results warrant further evaluation of the potential anti-SARS-CoV-2 activity of cepharanthine and nelfinavir.
