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).
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.
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