@article{4936e902c18448348bbbabea19d87805,
title = "Potential anti-COVID-19 agents, cepharanthine and nelfinavir, and their usage for combination treatment",
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.",
author = "Hirofumi Ohashi and Koichi Watashi and Wakana Saso and Kaho Shionoya and Shoya Iwanami and Takatsugu Hirokawa and Tsuyoshi Shirai and Shigehiko Kanaya and Yusuke Ito and Kim, {Kwang Su} and Takao Nomura and Tateki Suzuki and Kazane Nishioka and Shuji Ando and Keisuke Ejima and Yoshiki Koizumi and Tomohiro Tanaka and Shin Aoki and Kouji Kuramochi and Tadaki Suzuki and Takao Hashiguchi and Katsumi Maenaka and Tetsuro Matano and Masamichi Muramatsu and Masayuki Saijo and Kazuyuki Aihara and Shingo Iwami and Makoto Takeda and McKeating, {Jane A.} and Takaji Wakita",
note = "Funding Information: We thank Drs. Shuetsu Fukushi and Souichi Yamada at the Department of Virology I, National Institute of Infectious Diseases, Satoko Otsuguro, Dr. Manabu Nagao and Sayaka Niizuma at Hokkaido University, and Noriko Kurisaki at Kyushu University for technical assistance. NFV, LPV, and FPV were kindly provided by Japan Tobacco, Abbvie, and Fujifilm Toyama Chemical. Pharmaceutical preparation of CEP was kindly provided by Medisa Shinyaku Inc, a subsidiary of Sawai Pharmaceutical. This work was supported by the Agency for Medical Research and Development ( AMED ) emerging/re-emerging infectious diseases project ( JP19fk0108111 , JP19fk0108110 , JP20fk0108104 , JP20fk0108411 ); 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 KAKENHI ( JP17H04085 , JP20H03499 , JP15H05707 , 19H04839 ); the JST MIRAI Program; and the Wellcome Trust -funded Investigator award ( 200838/Z/16/Z ). Funding Information: We thank Drs. Shuetsu Fukushi and Souichi Yamada at the Department of Virology I, National Institute of Infectious Diseases, Satoko Otsuguro, Dr. Manabu Nagao and Sayaka Niizuma at Hokkaido University, and Noriko Kurisaki at Kyushu University for technical assistance. NFV, LPV, and FPV were kindly provided by Japan Tobacco, Abbvie, and Fujifilm Toyama Chemical. Pharmaceutical preparation of CEP was kindly provided by Medisa Shinyaku Inc, a subsidiary of Sawai Pharmaceutical. This work was supported by the Agency for Medical Research and Development (AMED) emerging/re-emerging infectious diseases project (JP19fk0108111, JP19fk0108110, JP20fk0108104, JP20fk0108411); 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 KAKENHI (JP17H04085, JP20H03499, JP15H05707, 19H04839); the JST MIRAI Program; and the Wellcome Trust-funded Investigator award (200838/Z/16/Z). Conceptualization, K.W.; investigation, H.O. K.W. W.S. K.S. S. Iwanami, T.H. T. Shirai. S.K. Y.I. K.S.K. T.N. Tateki Suzuki, K.N. and S. Iwami; methodology and resources, S.Ando. Tadaki Suzuki. T.H. K.M. M.S. M.T. T.W.; analysis, all the authors; writing and editing, K.W. T.H. K.A. S. Iwami, and J.A.M; funding acquisition, K.W. and M.T.; supervision, K.W. The authors declare no competing interests. Publisher Copyright: {\textcopyright} 2021 The Authors",
year = "2021",
month = apr,
day = "23",
doi = "10.1016/j.isci.2021.102367",
language = "English",
volume = "24",
journal = "iScience",
issn = "2589-0042",
publisher = "Elsevier Inc.",
number = "4",
}
