Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo
Abstract The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis. Clinical candidates with high efficacy, ready availability, and that do not develop resistance are in urgent need. Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture, there are few confirmed antiviral candidates in vivo. In this study, 94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs. Among them, 24 compounds with low cytotoxicity were selected, and of these, 17 compounds also effectively suppressed SARS-CoV-2 infection in HeLa cells transduced with human ACE2. Six compounds disturb multiple processes of the SARS-CoV-2 life cycle. Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2 infection. Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant. Except for cisatracurium, six compounds reduced hamster pulmonary viral load, and IL-6 and TNF-α mRNA when assayed at 4 d postinfection. In particular, sertraline, salinomycin, and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro, suggesting promising application for COVID-19 treatment..
Medienart: |
Artikel |
---|
Erscheinungsjahr: |
2021 |
---|---|
Erschienen: |
2021 |
Enthalten in: |
Zur Gesamtaufnahme - volume:65 |
---|---|
Enthalten in: |
Science China / Life sciences - 65(2021), 6 vom: 24. Dez., Seite 1181-1197 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Peng, Haoran [VerfasserIn] |
---|
Links: |
Volltext [lizenzpflichtig] |
---|
BKL: | |
---|---|
Themen: |
D614G variant |
Anmerkungen: |
© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021 |
---|
doi: |
10.1007/s11427-021-2031-7 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
OLC213081784X |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | OLC213081784X | ||
003 | DE-627 | ||
005 | 20240328065329.0 | ||
007 | tu | ||
008 | 230506s2021 xx ||||| 00| ||eng c | ||
024 | 7 | |a 10.1007/s11427-021-2031-7 |2 doi | |
035 | |a (DE-627)OLC213081784X | ||
035 | |a (DE-He213)s11427-021-2031-7-p | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
082 | 0 | 4 | |a 570 |q VZ |
082 | 0 | 4 | |a 570 |q VZ |
084 | |a 12 |2 ssgn | ||
084 | |a BIODIV |q DE-30 |2 fid | ||
084 | |a 42.00 |2 bkl | ||
100 | 1 | |a Peng, Haoran |e verfasserin |4 aut | |
245 | 1 | 0 | |a Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo |
264 | 1 | |c 2021 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ohne Hilfsmittel zu benutzen |b n |2 rdamedia | ||
338 | |a Band |b nc |2 rdacarrier | ||
500 | |a © Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2021 | ||
520 | |a Abstract The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis. Clinical candidates with high efficacy, ready availability, and that do not develop resistance are in urgent need. Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture, there are few confirmed antiviral candidates in vivo. In this study, 94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs. Among them, 24 compounds with low cytotoxicity were selected, and of these, 17 compounds also effectively suppressed SARS-CoV-2 infection in HeLa cells transduced with human ACE2. Six compounds disturb multiple processes of the SARS-CoV-2 life cycle. Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2 infection. Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant. Except for cisatracurium, six compounds reduced hamster pulmonary viral load, and IL-6 and TNF-α mRNA when assayed at 4 d postinfection. In particular, sertraline, salinomycin, and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro, suggesting promising application for COVID-19 treatment. | ||
650 | 4 | |a SARS-CoV-2 | |
650 | 4 | |a drug repurposing | |
650 | 4 | |a drug screening | |
650 | 4 | |a hamster model | |
650 | 4 | |a D614G variant | |
650 | 4 | |a drug resistance | |
700 | 1 | |a Ding, Cuiling |4 aut | |
700 | 1 | |a Jiang, Liangliang |4 aut | |
700 | 1 | |a Tang, Wanda |4 aut | |
700 | 1 | |a Liu, Yan |4 aut | |
700 | 1 | |a Zhao, Lanjuan |4 aut | |
700 | 1 | |a Yi, Zhigang |4 aut | |
700 | 1 | |a Ren, Hao |4 aut | |
700 | 1 | |a Li, Chong |4 aut | |
700 | 1 | |a He, Yanhua |4 aut | |
700 | 1 | |a Zheng, Xu |4 aut | |
700 | 1 | |a Tang, Hailin |4 aut | |
700 | 1 | |a Chen, Zhihui |4 aut | |
700 | 1 | |a Qi, Zhongtian |4 aut | |
700 | 1 | |a Zhao, Ping |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Science China / Life sciences |d Science China Press, 2010 |g 65(2021), 6 vom: 24. Dez., Seite 1181-1197 |w (DE-627)621553921 |w (DE-600)2544288-0 |w (DE-576)321913892 |x 1674-7305 |7 nnns |
773 | 1 | 8 | |g volume:65 |g year:2021 |g number:6 |g day:24 |g month:12 |g pages:1181-1197 |
856 | 4 | 1 | |u https://doi.org/10.1007/s11427-021-2031-7 |z lizenzpflichtig |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a SYSFLAG_A | ||
912 | |a GBV_OLC | ||
912 | |a FID-BIODIV | ||
912 | |a SSG-OLC-PHA | ||
912 | |a GBV_ILN_2018 | ||
912 | |a GBV_ILN_4082 | ||
936 | b | k | |a 42.00 |j Biologie: Allgemeines |j Biologie: Allgemeines |q VZ |
951 | |a AR | ||
952 | |d 65 |j 2021 |e 6 |b 24 |c 12 |h 1181-1197 |