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

Hirofumi Ohashi,Shoya Iwanami,Koichi Watashi,Wakana Saso,Kaho Shionoya,Kazuyuki Aihara,Takao Nomura,Kazane Nishioka,Tadaki Suzuki,Tateki Suzuki,Shin Aoki,Tomohiro Tanaka,Jane A Mckeating,Kouji Kuramochi,Masayuki Saijo,Katsumi Maenaka,Takaji Wakita,Shingo Iwami,Makoto Takeda,Keisuke Ejima,Shuji Ando,Masamichi Muramatsu,Shigehiko Kanaya,Kwang Su Kim,Takatsugu Hirokawa,Yoshiki Koizumi,Tetsuro Matano,Tomoyuki Shirai ,Takao Hanabusa ,Yasutaka Ito

doi:10.1016/j.isci.2021.102367

Abstract

SummaryAntiviral 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.

Highlights

The novel coronavirus disease 2019 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health problem that is impacting social and economic damage worldwide (Huang et al, 2020; Zhou et al, 2020; Zhu et al, 2020)
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 antiinflammatory drug cepharanthine and human immunodeficiency virus protease inhibitor nelfinavir
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

Summary

Introduction

The novel coronavirus disease 2019 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global public health problem that is impacting social and economic damage worldwide (Huang et al, 2020; Zhou et al, 2020; Zhu et al, 2020). We screened a panel of already approved drugs in a SARS-CoV-2 infection cell culture assay and identified two, cepharanthine (CEP) and nelfinavir (NFV), that showed more potent antiviral activity compared to RDV and other drugs currently being trialed. In silico, and cell culture analyses demonstrate that CEP and NFV inhibit SARS-CoV-2 entry and RNA replication, respectively. Their different modes of action provided synergistic antiviral effects. We mathematically predicted the potential antiviral efficacy of the single treatment of either CEP or NFV and its combination in clinical settings. These data cumulatively provide evidence for anti-SARS-CoV-2 potentials of CEP and NFV

Results

Discussion

Conclusion