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

被引：135

作者：

Ohashi, Hirofumi ^{[1
,2
]}

Watashi, Koichi ^{[1
,2
,3
,4
,29
]}

Saso, Wakana ^{[1
,5
,6
]}

Shionoya, Kaho ^{[1
,2
]}

Iwanami, Shoya ^{[7
]}

Hirokawa, Takatsugu ^{[8
,9
,10
]}

Shirai, Tsuyoshi ^{[11
]}

Kanaya, Shigehiko ^{[12
]}

Ito, Yusuke ^{[7
]}

Kim, Kwang Su ^{[7
]}

Nomura, Takao ^{[13
]}

Suzuki, Tateki ^{[14
]}

Nishioka, Kazane ^{[1
,2
]}

Ando, Shuji ^{[15
]}

Ejima, Keisuke ^{[16
]}

Koizumi, Yoshiki ^{[17
]}

Tanaka, Tomohiro ^{[18
]}

Aoki, Shin ^{[18
,19
]}

Kuramochi, Kouji ^{[2
]}

Suzuki, Tadaki ^{[20
]}

Hashiguchi, Takao ^{[14
]}

Maenaka, Katsumi ^{[13
,21
,22
]}

Matano, Tetsuro ^{[5
,6
]}

Muramatsu, Masamichi ^{[1
]}

Saijo, Masayuki ^{[15
]}

Aihara, Kazuyuki ^{[23
]}

Iwami, Shingo ^{[4
,7
,24
,25
,26
]}

Takeda, Makoto ^{[27
]}

McKeating, Jane A. ^{[28
]}

Wakita, Takaji ^{[1
]}

机构：

[1] Natl Inst Infect Dis, Dept Virol 2, Tokyo 1628640, Japan

[2] Tokyo Univ Sci, Dept Appl Biol Sci, Noda, Chiba 2788510, Japan

[3] Kyoto Univ, Inst Frontier Life & Med Sci, Kyoto 6068507, Japan

[4] JST, MIRAI, Kawaguchi, Saitama 3320012, Japan

[5] Univ Tokyo, Inst Med Sci, Tokyo 1088639, Japan

[6] Natl Inst Infect Dis, AIDS Res Ctr, Tokyo 1628640, Japan

[7] Kyushu Univ, Fac Sci, Dept Biol, Fukuoka 8128581, Japan

[8] Natl Inst Adv Ind Sci & Technol, Cellular & Mol Biotechnol Res Inst, Tokyo 1350064, Japan

[9] Univ Tsukuba, Fac Med, Div Biomed Sci, Tsukuba, Ibaraki 3058575, Japan

[10] Univ Tsukuba, Transborder Med Res Ctr, Tsukuba, Ibaraki 3058575, Japan

[11] Nagahama Inst Biosci & Technol, Fac Biosci, Nagahama 5260829, Japan

[12] Nara Inst Sci & Technol, Grad Sch Sci & Technol, Ikoma 6300192, Japan

[13] Hokkaido Univ, Fac Pharmaceut Sci, Ctr Res & Educ Drug Discovery, Sapporo, Hokkaido 0600812, Japan

[14] Kyushu Univ, Fac Med, Dept Virol, Fukuoka 8128582, Japan

[15] Natl Inst Infect Dis, Dept Virol 1, Tokyo 1628640, Japan

[16] Indiana Univ, Dept Epidemiol & Biostat, Sch Publ Hlth Bloomington, Bloomington, IN 47405 USA

[17] Natl Ctr Global Hlth & Med, Tokyo 1628655, Japan

[18] Tokyo Univ Sci, Fac Pharmaceut Sci, Noda, Chiba 2788510, Japan

[19] Tokyo Univ Sci, Res Inst Sci & Technol, Noda, Chiba 2788510, Japan

[20] Natl Inst Infect Dis, Dept Pathol, Tokyo 1628640, Japan

[21] Hokkaido Univ, Fac Pharmaceut Sci, Lab Biomol Sci, Sapporo, Hokkaido 0600812, Japan

[22] Hokkaido Univ, Ctr Life Innovat, Global Stn Biosurfaces & Drug Discovery, Sapporo, Hokkaido 0600812, Japan

[23] Univ Tokyo, Univ Tokyo Inst Adv Study, Int Res Ctr Neurointelligence, Tokyo 1138654, Japan

[24] Kyoto Univ, Inst Adv Study Human Biol ASHBi, Kyoto 6068501, Japan

[25] Japanese Fdn Canc Res JFCR, NEXT Ganken Program, Tokyo 1358550, Japan

[26] Sci Groove Inc, Fukuoka 8100041, Japan

[27] Natl Inst Infect Dis, Dept Virol 3, Tokyo 2080011, Japan

[28] Univ Oxford, Nuffield Dept Med, Oxford OX3 7FZ, England

[29] Natl Inst Infect Dis, Res Ctr Drug & Vaccine Dev, Tokyo 1628640, Japan

来源：

ISCIENCE | 2021年 / 24卷 / 04期

基金：

英国惠康基金; 日本学术振兴会;

关键词：

ACCURATE DOCKING; DRUGS; SARS; INHIBITOR; PROTEASE; PHARMACOKINETICS; REPLICATION; SARS-COV-2; COVID-19; GLIDE;

D O I：

10.1016/j.isci.2021.102367

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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.

引用

页数：28

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