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Multidrug treatment with nelfinavir and cepharanthine against COVID-19

Hirofumi Ohashi, Koichi Watashi, Wakana Saso, Kaho Shionoya, Shoya Iwanami, Takatsugu Hirokawa, Tsuyoshi Shirai, Shigehiko Kanaya, Yusuke Ito, Kwang Su Kim, Kazane Nishioka, Shuji Ando, Keisuke Ejima, Yoshiki Koizumi, Tomohiro Tanaka, Shin Aoki, Kouji Kuramochi, Tadaki Suzuki, Katsumi Maenaka, Tetsuro Matano, Masamichi Muramatsu, Masayuki Saijo, Kazuyuki Aihara, Shingo Iwami, Makoto Takeda, Jane A. McKeating, Takaji Wakita
doi: https://doi.org/10.1101/2020.04.14.039925
Hirofumi Ohashi
1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
2Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
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Koichi Watashi
1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
2Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
3Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan
4MIRAI, JST, Saitama 332-0012, Japan
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  • For correspondence: kwatashi@nih.go.jp
Wakana Saso
1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
5The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
6AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Kaho Shionoya
1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
2Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
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Shoya Iwanami
7Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
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Takatsugu Hirokawa
8Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan
9Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
10Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan
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Tsuyoshi Shirai
11Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan
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Shigehiko Kanaya
12Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 630-0192, Japan
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Yusuke Ito
7Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
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Kwang Su Kim
7Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
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Kazane Nishioka
1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
2Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
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Shuji Ando
13Department of Virology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Keisuke Ejima
14Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, IN 47405, USA
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Yoshiki Koizumi
15National Center for Global Health and Medicine, Tokyo162-8655, Japan
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Tomohiro Tanaka
16Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
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Shin Aoki
16Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan
17Research Institute for Science and Technology, Tokyo University of Science, Noda 278-8510, Japan
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Kouji Kuramochi
2Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan
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Tadaki Suzuki
18Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Katsumi Maenaka
19Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan
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Tetsuro Matano
5The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan
6AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Masamichi Muramatsu
1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Masayuki Saijo
13Department of Virology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Kazuyuki Aihara
20International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-8654, Japan
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Shingo Iwami
4MIRAI, JST, Saitama 332-0012, Japan
7Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan
21Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan
22NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan
23Science Groove Inc., Fukuoka 810-0041, Japan
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Makoto Takeda
24Department of Virology III, National Institute of Infectious Diseases, Tokyo 208-0011, Japan
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Jane A. McKeating
25Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK
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Takaji Wakita
1Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan
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Summary

Antiviral treatments targeting the emerging coronavirus disease 2019 (COVID-19) 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 antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. Consistent with their different modes of action, in vitro assays highlight a synergistic effect of this combined treatment to limit SARS-CoV-2 proliferation. Mathematical modeling in vitro antiviral activity coupled with the known pharmacokinetics for these drugs predicts that Nelfinavir will facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.

Competing Interest Statement

The authors have declared no competing interest.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission.
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Posted April 15, 2020.
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Multidrug treatment with nelfinavir and cepharanthine against COVID-19
Hirofumi Ohashi, Koichi Watashi, Wakana Saso, Kaho Shionoya, Shoya Iwanami, Takatsugu Hirokawa, Tsuyoshi Shirai, Shigehiko Kanaya, Yusuke Ito, Kwang Su Kim, Kazane Nishioka, Shuji Ando, Keisuke Ejima, Yoshiki Koizumi, Tomohiro Tanaka, Shin Aoki, Kouji Kuramochi, Tadaki Suzuki, Katsumi Maenaka, Tetsuro Matano, Masamichi Muramatsu, Masayuki Saijo, Kazuyuki Aihara, Shingo Iwami, Makoto Takeda, Jane A. McKeating, Takaji Wakita
bioRxiv 2020.04.14.039925; doi: https://doi.org/10.1101/2020.04.14.039925
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Multidrug treatment with nelfinavir and cepharanthine against COVID-19
Hirofumi Ohashi, Koichi Watashi, Wakana Saso, Kaho Shionoya, Shoya Iwanami, Takatsugu Hirokawa, Tsuyoshi Shirai, Shigehiko Kanaya, Yusuke Ito, Kwang Su Kim, Kazane Nishioka, Shuji Ando, Keisuke Ejima, Yoshiki Koizumi, Tomohiro Tanaka, Shin Aoki, Kouji Kuramochi, Tadaki Suzuki, Katsumi Maenaka, Tetsuro Matano, Masamichi Muramatsu, Masayuki Saijo, Kazuyuki Aihara, Shingo Iwami, Makoto Takeda, Jane A. McKeating, Takaji Wakita
bioRxiv 2020.04.14.039925; doi: https://doi.org/10.1101/2020.04.14.039925

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