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Identification of Anti-COVID-19 Agents, Cepharanthine and Nelfinavir, and Their Potential Usage for Combination Treatment

36 Pages Posted: 23 Jun 2020 Publication Status: Under Review

See all articles by Hirofumi Ohashi

Hirofumi Ohashi

National Institute of Infectious Diseases - Department of Virology II

Koichi Watashi

National Institute of Infectious Diseases - Department of Virology II

Wakana Saso

National Institute of Infectious Diseases - Department of Virology II

Kaho Shionoya

National Institute of Infectious Diseases - Department of Virology II

Shoya Iwanami

Kyushu University - Department of Biology

Takatsugu Hirokawa

National Institute of Advanced Industrial Science and Technology (AIST) - Cellular and Molecular Biotechnology Research Institute

Takehisa Matsumoto

RIKEN Center for Biosystems Dynamics Research - Drug Discovery Structural Biology Platform Unit

Tsuyoshi Shirai

Nagahama Institute of Bio-Science and Technology - Department of Bioscience

Shigehiko Kanaya

Nara Institute of Science and Technology - Graduate School of Science and Technology

Yusuke Ito

Kyushu University - Department of Biology

Kwang Su Kim

Kyushu University - Department of Biology

Takao Nomura

Hokkaido University - Center for Research and Education on Drug Discovery

Tateki Suzuki

Kyushu University - Department of Virology

Kazane Nishioka

National Institute of Infectious Diseases - Department of Virology II

Shuji Ando

National Institute of Infectious Diseases - Department of Virology I

Keisuke Ejima

ndiana University Bloomington - Department of Epidemiology and Biostatistics

Yoshiki Koizumi

National Center for Global Health and Medicine

Tomohiro Tanaka

Tokyo University of Science - Faculty of Pharmaceutical Sciences

Shin Aoki

Tokyo University of Science - Faculty of Pharmaceutical Sciences

Kouji Kuramochi

Tokyo University of Science - Department of Applied Biological Science

Tadaki Suzuki

National Institute of Infectious Diseases - Department of Pathology

Mikako Shirouzu

RIKEN Center for Life Science Technologies - Division of Structural and Synthetic Biology

Takao Hashiguchi

Kyushu University - Department of Virology

Katsumi Maenaka

Hokkaido University - Faculty of Pharmaceutical Sciences

Tetsuro Matano

National Institute of Infectious Diseases - AIDS Research Center

Masamichi Muramatsu

National Institute of Infectious Diseases - Department of Virology II

Masayuki Saijo

National Institute of Infectious Diseases - Department of Virology I

Kazuyuki Aihara

University of Tokyo - International Research Center for Neurointelligence

Shingo Iwami

Kyushu University - Department of Biology

Makoto Takeda

National Institute of Infectious Diseases - Department of Virology III

Jane A. Mckeating

University of Oxford - Nuffield Department of Medicine

Takaji Wakita

National Institute of Infectious Diseases - Department of Virology II

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Abstract

Antiviral treatments targeting the 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 agents having higher antiviral potentials than the drug candidates such as remdesivir and chroloquine: the anti-inflammatory drug Cepharanthine and HIV protease inhibitor Nelfinavir.  Cepharanthine inhibited SARS-CoV-2 entry into cells, whilst Nelfinavir inhibited the catalytic activity of viral main protease to suppress viral replication.  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 shorten the period until viral clearance by 5.5-days and the combining Cepharanthine/Nelfinavir enhanced their predicted efficacy to control viral proliferation. In summary, this study identifies a new multidrug combination treatment for COVID-19.

Funding: This work was supported by The Agency for Medical Research and Development (AMED) emerging/re-emerging infectious diseases project (JP19fk0108111, JP19fk0108110, JP20fk0108104); the AMED Basis for Supporting Innovative Drug Discovery and Life Science Research (BINDS, JP19am0101114, JP19am0101069, JP19am0101111) program; The Japan Society for the Promotion of Science 260 KAKENHI (JP17H04085, JP20H03499, JP15H05707, 19H04839); The JST MIRAI program; and Wellcome Trust funded Investigator award (200838/Z/16/Z).

Conflict of Interest: None.

Keywords: coronavirus, SARS-CoV-2, COVID-19, antiviral, Nelfinavir, Cepharanthine, protease, spike, in silico

Suggested Citation

Ohashi, Hirofumi and Watashi, Koichi and Saso, Wakana and Shionoya, Kaho and Iwanami, Shoya and Hirokawa, Takatsugu and Matsumoto, Takehisa and Shirai, Tsuyoshi and Kanaya, Shigehiko and Ito, Yusuke and Kim, Kwang Su and Nomura, Takao and Suzuki, Tateki and Nishioka, Kazane and Ando, Shuji and Ejima, Keisuke and Koizumi, Yoshiki and Tanaka, Tomohiro and Aoki, Shin and Kuramochi, Kouji and Suzuki, Tadaki and Shirouzu, Mikako and Hashiguchi, Takao and Maenaka, Katsumi and Matano, Tetsuro and Muramatsu, Masamichi and Saijo, Masayuki and Aihara, Kazuyuki and Iwami, Shingo and Takeda, Makoto and Mckeating, Jane A. and Wakita, Takaji, Identification of Anti-COVID-19 Agents, Cepharanthine and Nelfinavir, and Their Potential Usage for Combination Treatment. Available at SSRN: https://ssrn.com/abstract=3631397 or http://dx.doi.org/10.2139/ssrn.3631397
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Hirofumi Ohashi

National Institute of Infectious Diseases - Department of Virology II ( email )

Japan

Koichi Watashi (Contact Author)

National Institute of Infectious Diseases - Department of Virology II

1-23-1 Toyama Shinjuku Yokyo
Japan

Wakana Saso

National Institute of Infectious Diseases - Department of Virology II ( email )

Japan

Kaho Shionoya

National Institute of Infectious Diseases - Department of Virology II ( email )

Japan

Shoya Iwanami

Kyushu University - Department of Biology ( email )

Fukuoka, 819-0395
Japan

Takatsugu Hirokawa

National Institute of Advanced Industrial Science and Technology (AIST) - Cellular and Molecular Biotechnology Research Institute ( email )

1-3-1 Kasumigaseki
Chiyoda-ku
Tokyo, 100-8921
Japan

Takehisa Matsumoto

RIKEN Center for Biosystems Dynamics Research - Drug Discovery Structural Biology Platform Unit ( email )

2-2-3 Minatojima Minami-machi
Chuou-ku, Kobe
Hyogo 650-0047
Japan

Tsuyoshi Shirai

Nagahama Institute of Bio-Science and Technology - Department of Bioscience

1266, 田村町
Nagahama, Shiga, 526-0829
Japan

Shigehiko Kanaya

Nara Institute of Science and Technology - Graduate School of Science and Technology ( email )

5 Takayamacho
Ikoma, 630-0192
Japan

Yusuke Ito

Kyushu University - Department of Biology ( email )

Fukuoka, 819-0395
Japan

Kwang Su Kim

Kyushu University - Department of Biology ( email )

Fukuoka, 819-0395
Japan

Takao Nomura

Hokkaido University - Center for Research and Education on Drug Discovery ( email )

5 Kita 8 Jonishi, Kita Ward
Hokkaido Prefecture
Sapporo, Hokkaido 060-0808
Japan

Tateki Suzuki

Kyushu University - Department of Virology ( email )

6-19-1, Hakozaki, Higashiku
Fukuoka, 812-8581
Japan

Kazane Nishioka

National Institute of Infectious Diseases - Department of Virology II ( email )

Japan

Shuji Ando

National Institute of Infectious Diseases - Department of Virology I ( email )

1-23-1 Toyama Shinjuku Yokyo
Japan

Keisuke Ejima

ndiana University Bloomington - Department of Epidemiology and Biostatistics ( email )

IN
United States

Yoshiki Koizumi

National Center for Global Health and Medicine ( email )

Tokyo 162-8655
Japan

Tomohiro Tanaka

Tokyo University of Science - Faculty of Pharmaceutical Sciences

1-3 Kagurazaka
Tokyo, 162-8601
Japan

Shin Aoki

Tokyo University of Science - Faculty of Pharmaceutical Sciences

1-3 Kagurazaka
Tokyo, 162-8601
Japan

Kouji Kuramochi

Tokyo University of Science - Department of Applied Biological Science ( email )

1-3 Kagurazaka
Tokyo, 162-8601
Japan

Tadaki Suzuki

National Institute of Infectious Diseases - Department of Pathology

Japan

Mikako Shirouzu

RIKEN Center for Life Science Technologies - Division of Structural and Synthetic Biology ( email )

1-7-22 Suehiro-cho
Tsurumi, Yokohama 230-0045
Japan

Takao Hashiguchi

Kyushu University - Department of Virology ( email )

6-19-1, Hakozaki, Higashiku
Fukuoka, 812-8581
Japan

Katsumi Maenaka

Hokkaido University - Faculty of Pharmaceutical Sciences ( email )

Japan

Tetsuro Matano

National Institute of Infectious Diseases - AIDS Research Center

1-23-1 Toyama Shinjuku Yokyo
Japan

Masamichi Muramatsu

National Institute of Infectious Diseases - Department of Virology II ( email )

Japan

Masayuki Saijo

National Institute of Infectious Diseases - Department of Virology I ( email )

1-23-1 Toyama Shinjuku Yokyo
Japan

Kazuyuki Aihara

University of Tokyo - International Research Center for Neurointelligence

Yayoi 1-1-1
Bunkyo-ku
Tokyo, Tokyo 113-8657
Japan

Shingo Iwami

Kyushu University - Department of Biology ( email )

Fukuoka, 819-0395
Japan

Makoto Takeda

National Institute of Infectious Diseases - Department of Virology III

1-23-1 Toyama Shinjuku Yokyo
Japan

Jane A. Mckeating

University of Oxford - Nuffield Department of Medicine ( email )

Old Road Campus
Roosevelt Drive
Oxford, OX3 7FZ
United Kingdom

Takaji Wakita

National Institute of Infectious Diseases - Department of Virology II ( email )

Japan

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