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

doi:10.1016/j.isci.2021.102367

Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment

iScience. 2021 Apr 23;24(4):102367. doi: 10.1016/j.isci.2021.102367. Epub 2021 Mar 26.

Authors

Hirofumi Ohashi^{1

2}, Koichi Watashi^{1

2

3

4

5}, Wakana Saso^{1

6

7}, Kaho Shionoya^{1

2}, Shoya Iwanami⁸, Takatsugu Hirokawa^{9

10

11}, Tsuyoshi Shirai¹², Shigehiko Kanaya¹³, Yusuke Ito⁸, Kwang Su Kim⁸, Takao Nomura¹⁴, Tateki Suzuki¹⁵, Kazane Nishioka^{1

2}, Shuji Ando¹⁶, Keisuke Ejima¹⁷, Yoshiki Koizumi¹⁸, Tomohiro Tanaka¹⁹, Shin Aoki^{19

20}, Kouji Kuramochi², Tadaki Suzuki²¹, Takao Hashiguchi¹⁵, Katsumi Maenaka^{14

22

23}, Tetsuro Matano^{6

7}, Masamichi Muramatsu¹, Masayuki Saijo¹⁶, Kazuyuki Aihara²⁴, Shingo Iwami^{4

8

25

26

27}, Makoto Takeda²⁸, Jane A McKeating²⁹, Takaji Wakita¹

Affiliations

¹ Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
² Department of Applied Biological Science, Tokyo University of Science, Noda 278-8510, Japan.
³ Institute for Frontier Life and Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
⁴ MIRAI, JST, Saitama 332-0012, Japan.
⁵ Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
⁶ The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
⁷ AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
⁸ Department of Biology, Faculty of Sciences, Kyushu University, Fukuoka 812-8581, Japan.
⁹ Cellular and Molecular Biotechnology Research Institute, National Institute of Advanced Industrial Science and Technology, Tokyo 135-0064, Japan.
¹⁰ Division of Biomedical Science, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan.
¹¹ Transborder Medical Research Center, University of Tsukuba, Tsukuba 305-8575, Japan.
¹² Faculty of Bioscience, Nagahama Institute of Bio-Science and Technology, Nagahama 526-0829, Japan.
¹³ Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma 630-0192, Japan.
¹⁴ Center for Research and Education on Drug Discovery, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
¹⁵ Department of Virology, Faculty of Medicine, Kyushu University, Fukuoka 812-8582, Japan.
¹⁶ Department of Virology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
¹⁷ Department of Epidemiology and Biostatistics, Indiana University School of Public Health-Bloomington, Bloomington, IN 47405, USA.
¹⁸ National Center for Global Health and Medicine, Tokyo 162-8655, Japan.
¹⁹ Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda 278-8510, Japan.
²⁰ Research Institute for Science and Technology, Tokyo University of Science, Noda 278-8510, Japan.
²¹ Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
²² Laboratory of Biomolecular Science, Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo 060-0812, Japan.
²³ Global Station for Biosurfaces and Drug Discovery, Center for Life Innovation, Hokkaido University, Sapporo 060-0812, Japan.
²⁴ International Research Center for Neurointelligence, The University of Tokyo Institutes for Advanced Study, The University of Tokyo, Tokyo 113-8654, Japan.
²⁵ Institute for the Advanced Study of Human Biology (ASHBi), Kyoto University, Kyoto 606-8501, Japan.
²⁶ NEXT-Ganken Program, Japanese Foundation for Cancer Research (JFCR), Tokyo 135-8550, Japan.
²⁷ Science Groove Inc., Fukuoka 810-0041, Japan.
²⁸ Department of Virology III, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
²⁹ Nuffield Department of Medicine, University of Oxford, Oxford OX3 7FZ, UK.

Abstract

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.

Keywords: Medical Substance; Pharmaceutical Preparation; Virology.

Abstract

Grants and funding