All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity
The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and...
| Main Authors: | , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2021-08-01
|
| Series: | Viruses |
| Subjects: | |
| Online Access: | https://www.mdpi.com/1999-4915/13/8/1669 |
| _version_ | 1797521773954072576 |
|---|---|
| author | Takeshi Morita Kei Miyakawa Sundararaj Stanleyraj Jeremiah Yutaro Yamaoka Mitsuru Sada Tomoko Kuniyoshi Jinwei Yang Hirokazu Kimura Akihide Ryo |
| author_facet | Takeshi Morita Kei Miyakawa Sundararaj Stanleyraj Jeremiah Yutaro Yamaoka Mitsuru Sada Tomoko Kuniyoshi Jinwei Yang Hirokazu Kimura Akihide Ryo |
| author_sort | Takeshi Morita |
| collection | DOAJ |
| description | The pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found that all-trans retinoic acid (ATRA), an FDA-approved drug, inhibited 3CLpro activity. The 3CLpro inhibitory effect of ATRA was confirmed in vitro by both immunoblotting and AlphaScreen with a 50% inhibition concentration (IC<sub>50</sub>) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC<sub>50</sub> = 2.69 ± 0.09 µM in the former and 0.82 ± 0.01 µM in the latter. Further, we showed the anti-SARS-CoV-2 effect of ATRA on the currently circulating variants of concern (VOC); alpha, beta, gamma, and delta. These results suggest that ATRA may be considered as a potential therapeutic agent against SARS-CoV-2. |
| first_indexed | 2024-03-10T08:17:20Z |
| format | Article |
| id | doaj.art-26bed291b85a41bb9c5b6483cc38d2e8 |
| institution | Directory Open Access Journal |
| issn | 1999-4915 |
| language | English |
| last_indexed | 2024-03-10T08:17:20Z |
| publishDate | 2021-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Viruses |
| spelling | doaj.art-26bed291b85a41bb9c5b6483cc38d2e82023-11-22T10:13:04ZengMDPI AGViruses1999-49152021-08-01138166910.3390/v13081669All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro ActivityTakeshi Morita0Kei Miyakawa1Sundararaj Stanleyraj Jeremiah2Yutaro Yamaoka3Mitsuru Sada4Tomoko Kuniyoshi5Jinwei Yang6Hirokazu Kimura7Akihide Ryo8Department of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, JapanDepartment of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, JapanDepartment of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, JapanDepartment of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, JapanAdvanced Medical Science Research Center, Gunma Paz University, Shibukawa 377-0008, JapanR&D Department, TOKIWA Phytochemical Co., Ltd., Sakura, Chiba 285-0801, JapanR&D Department, TOKIWA Phytochemical Co., Ltd., Sakura, Chiba 285-0801, JapanDepartment of Health Science, Gunma Paz University Graduate School, Takasaki 370-0006, JapanDepartment of Microbiology, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, JapanThe pandemic of COVID-19 caused by SARS-CoV-2 continues to spread despite the global efforts taken to control it. The 3C-like protease (3CLpro), the major protease of SARS-CoV-2, is one of the most interesting targets for antiviral drug development because it is highly conserved among SARS-CoVs and plays an important role in viral replication. Herein, we developed high throughput screening for SARS-CoV-2 3CLpro inhibitor based on AlphaScreen. We screened 91 natural product compounds and found that all-trans retinoic acid (ATRA), an FDA-approved drug, inhibited 3CLpro activity. The 3CLpro inhibitory effect of ATRA was confirmed in vitro by both immunoblotting and AlphaScreen with a 50% inhibition concentration (IC<sub>50</sub>) of 24.7 ± 1.65 µM. ATRA inhibited the replication of SARS-CoV-2 in VeroE6/TMPRSS2 and Calu-3 cells, with IC<sub>50</sub> = 2.69 ± 0.09 µM in the former and 0.82 ± 0.01 µM in the latter. Further, we showed the anti-SARS-CoV-2 effect of ATRA on the currently circulating variants of concern (VOC); alpha, beta, gamma, and delta. These results suggest that ATRA may be considered as a potential therapeutic agent against SARS-CoV-2.https://www.mdpi.com/1999-4915/13/8/16693CL proteasehigh throughput screeningall-trans retinoic acidFDA-approved drugantiviral efficacySARS-CoV-2 |
| spellingShingle | Takeshi Morita Kei Miyakawa Sundararaj Stanleyraj Jeremiah Yutaro Yamaoka Mitsuru Sada Tomoko Kuniyoshi Jinwei Yang Hirokazu Kimura Akihide Ryo All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity Viruses 3CL protease high throughput screening all-trans retinoic acid FDA-approved drug antiviral efficacy SARS-CoV-2 |
| title | All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity |
| title_full | All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity |
| title_fullStr | All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity |
| title_full_unstemmed | All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity |
| title_short | All-Trans Retinoic Acid Exhibits Antiviral Effect against SARS-CoV-2 by Inhibiting 3CLpro Activity |
| title_sort | all trans retinoic acid exhibits antiviral effect against sars cov 2 by inhibiting 3clpro activity |
| topic | 3CL protease high throughput screening all-trans retinoic acid FDA-approved drug antiviral efficacy SARS-CoV-2 |
| url | https://www.mdpi.com/1999-4915/13/8/1669 |
| work_keys_str_mv | AT takeshimorita alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT keimiyakawa alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT sundararajstanleyrajjeremiah alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT yutaroyamaoka alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT mitsurusada alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT tomokokuniyoshi alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT jinweiyang alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT hirokazukimura alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity AT akihideryo alltransretinoicacidexhibitsantiviraleffectagainstsarscov2byinhibiting3clproactivity |