Multidrug treatment with nelfinavir and cepharanthine against COVID-19

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

Antiviral treatments targeting the emerging 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 antiviral agents: the HIV protease inhibitor Nelfinavir and the anti-inflammatory drug Cepharanthine. In silico modeling shows Nelfinavir binds the SARS-CoV-2 main protease consistent with its inhibition of viral replication, whilst Cepharanthine inhibits viral attachment and entry into cells. 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 facilitate viral clearance. Combining Nelfinavir/Cepharanthine enhanced their predicted efficacy to control viral proliferation, to ameliorate both the progression of disease and risk of transmission. In summary, this study identifies a new multidrug combination treatment for COVID-19.