| RRC ID |
85797
|
| 著者 |
Toba S, Uemura K, Sanaki T, Kusakabe S, Konishi K, Miki S, Maruyama Y, Iimuro A, Shishido T, Sasaki M, Orba Y, Hall WW, Sawa H, Sato A.
|
| タイトル |
Synergistic antiviral activity of a cathepsin B/L inhibitor and a TMPRSS2 inhibitor against SARS-CoV-2 in vitro and in vivo.
|
| ジャーナル |
Virology
|
| Abstract |
The spike (S) protein of Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) binds to a host cell receptor which dictates the viral entry pathway. SARS-CoV-2 utilizes two different pathways for cellular entry mediated by both a host type II transmembrane serine protease (TMPRSS2) and cathepsin proteases. These host proteases cleave the viral S protein and initiate membrane fusion allowing viral infection. We previously isolated a SARS-CoV-2 mutant with deletion in the furin cleavage site of the S gene (del2) and revealed differences in cell tropism between wild-type (WT) and del2 viruses. Here, we evaluated the antiviral activities of cellular protease inhibitors against SARS-CoV-2 WT and del2 viruses using several different cell lines. The TMPRSS2 inhibitor, camostat, exhibited strong antiviral activity against WT virus but not del2, while the cathepsin B/L inhibitor, K11777, exhibited potent antiviral activity against the del2 virus. We isolated K11777-escape mutants of SARS-CoV-2 and SARS-CoV and demonstrated that these mutations facilitated S protein cleavage at the S2' site mediated by cathepsin L. Finally, we demonstrated that combination treatment of K11777 and camostat potently inhibited SARS-CoV-2 WT infection in vitro and in vivo, suggesting the usefulness of combination therapeutics targeting host TMPRSS2 and cathepsin proteases against coronavirus infection. In summary, our study characterized K11777 as an inhibitor of S2' cleavage by cathepsins, highlighting the critical role of the S2' site in SARS-CoV-2 cellular entry. This research sheds light on the infection process and has implications for potential therapeutic interventions for SARS-CoV-2 infection.
|
| 巻・号 |
612
|
| ページ |
110661
|
| 公開日 |
2025-8-21
|
| DOI |
10.1016/j.virol.2025.110661
|
| PII |
S0042-6822(25)00274-0
|
| PMID |
40902217
|
| MeSH |
Animals
Antiviral Agents* / pharmacology
COVID-19 / virology
COVID-19 Drug Treatment*
Cathepsin B* / antagonists & inhibitors
Cathepsin L* / antagonists & inhibitors
Cell Line
Chlorocebus aethiops
Drug Synergism
Esters
Guanidines* / pharmacology
Humans
Mice
SARS-CoV-2* / drug effects
SARS-CoV-2* / genetics
Serine Endopeptidases* / metabolism
Spike Glycoprotein, Coronavirus / genetics
Spike Glycoprotein, Coronavirus / metabolism
Vero Cells
Virus Internalization / drug effects
|
| IF |
2.819
|
| リソース情報 |
| ヒト・動物細胞 |
293T(RCB2202) |
| 遺伝子材料 |
CSII-CMV-MCS-IRES2-Bsd (RDB04385) |
