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iScience
. 2021 Mar 26;102367.
doi: 10.1016/j.isci.2021.102367. Online ahead of print.
Potential anti-COVID-19 agents, Cepharanthine and Nelfinavir, and their usage for combination treatment
Hirofumi Ohashi 1 2 , Koichi Watashi 1 2 3 4 , Wakana Saso 1 5 6 , Kaho Shionoya 1 2 , Shoya Iwanami 7 , Takatsugu Hirokawa 8 9 10 , Tsuyoshi Shirai 11 , Shigehiko Kanaya 12 , Yusuke Ito 7 , Kwang Su Kim 7 , Takao Nomura 13 , Tateki Suzuki 14 , Kazane Nishioka 1 2 , Shuji Ando 15 , Keisuke Ejima 16 , Yoshiki Koizumi 17 , Tomohiro Tanaka 18 , Shin Aoki 18 19 , Kouji Kuramochi 2 , Tadaki Suzuki 20 , Takao Hashiguchi 14 , Katsumi Maenaka 13 21 22 , Tetsuro Matano 5 6 , Masamichi Muramatsu 1 , Masayuki Saijo 15 , Kazuyuki Aihara 23 , Shingo Iwami 4 7 24 25 26 , Makoto Takeda 27 , Jane A McKeating 28 , Takaji Wakita 1
Affiliations
- PMID: 33817567
- PMCID: PMC7997640
- DOI: 10.1016/j.isci.2021.102367
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 HIV protease inhibitor Nelfinavir. Cepharanthine inhibited SARS-CoV-2 entry through the blocking of viral binding to target cells, whilst 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: COVID-19; Cepharanthine; Nelfinavir; SARS-CoV-2; Spike; antiviral; coronavirus; in silico; protease; replication.