Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro
The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives o...
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| Format: | Article |
| Language: | English |
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MDPI AG
2021-03-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/22/6/3163 |
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| author | Hirofumi Ohashi Feng Wang Frank Stappenbeck Kana Tsuchimoto Chisa Kobayashi Wakana Saso Michiyo Kataoka Masako Yamasaki Kouji Kuramochi Masamichi Muramatsu Tadaki Suzuki Camille Sureau Makoto Takeda Takaji Wakita Farhad Parhami Koichi Watashi |
| author_facet | Hirofumi Ohashi Feng Wang Frank Stappenbeck Kana Tsuchimoto Chisa Kobayashi Wakana Saso Michiyo Kataoka Masako Yamasaki Kouji Kuramochi Masamichi Muramatsu Tadaki Suzuki Camille Sureau Makoto Takeda Takaji Wakita Farhad Parhami Koichi Watashi |
| author_sort | Hirofumi Ohashi |
| collection | DOAJ |
| description | The development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(<i>R</i>)-hydroxycholesterol, 24(<i>S</i>)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19. |
| first_indexed | 2024-03-10T13:04:05Z |
| format | Article |
| id | doaj.art-a998174f28e94e449274955719896c32 |
| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-10T13:04:05Z |
| publishDate | 2021-03-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | International Journal of Molecular Sciences |
| spelling | doaj.art-a998174f28e94e449274955719896c322023-11-21T11:16:18ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672021-03-01226316310.3390/ijms22063163Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In VitroHirofumi Ohashi0Feng Wang1Frank Stappenbeck2Kana Tsuchimoto3Chisa Kobayashi4Wakana Saso5Michiyo Kataoka6Masako Yamasaki7Kouji Kuramochi8Masamichi Muramatsu9Tadaki Suzuki10Camille Sureau11Makoto Takeda12Takaji Wakita13Farhad Parhami14Koichi Watashi15Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanMAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USAMAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USADepartment of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanDepartment of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanDepartment of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanDepartment of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, JapanDepartment of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanDepartment of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, JapanDepartment of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanDepartment of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, JapanLaboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine, 75739 Paris, FranceDepartment of Virology III, National Institute of Infectious Diseases, Tokyo 208-0011, JapanDepartment of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanMAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USADepartment of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, JapanThe development of effective antiviral drugs targeting the severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) is urgently needed to combat the coronavirus disease 2019 (COVID-19). We have previously studied the use of semi-synthetic derivatives of oxysterols, oxidized derivatives of cholesterol as drug candidates for the inhibition of cancer, fibrosis, and bone regeneration. In this study, we screened a panel of naturally occurring and semi-synthetic oxysterols for anti-SARS-CoV-2 activity using a cell culture infection assay. We show that the natural oxysterols, 7-ketocholesterol, 22(<i>R</i>)-hydroxycholesterol, 24(<i>S</i>)-hydroxycholesterol, and 27-hydroxycholesterol, substantially inhibited SARS-CoV-2 propagation in cultured cells. Among semi-synthetic oxysterols, Oxy210 and Oxy232 displayed more robust anti-SARS-CoV-2 activities, reducing viral replication more than 90% at 10 μM and 99% at 15 μM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 μM), based on the dose-dependent curve for antiviral activity in our cell-based assay. Mechanistic studies suggest that Oxy210 reduced replication of SARS-CoV-2 by disrupting the formation of double-membrane vesicles (DMVs); intracellular membrane compartments associated with viral replication. Our study warrants further evaluation of Oxy210 and Oxy232 as a safe and reliable oral medication, which could help protect vulnerable populations with increased risk of developing COVID-19.https://www.mdpi.com/1422-0067/22/6/3163SARS-CoV-2COVID-19oxysterolsantiviralcoronavirusdouble membrane vesicle |
| spellingShingle | Hirofumi Ohashi Feng Wang Frank Stappenbeck Kana Tsuchimoto Chisa Kobayashi Wakana Saso Michiyo Kataoka Masako Yamasaki Kouji Kuramochi Masamichi Muramatsu Tadaki Suzuki Camille Sureau Makoto Takeda Takaji Wakita Farhad Parhami Koichi Watashi Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro International Journal of Molecular Sciences SARS-CoV-2 COVID-19 oxysterols antiviral coronavirus double membrane vesicle |
| title | Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro |
| title_full | Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro |
| title_fullStr | Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro |
| title_full_unstemmed | Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro |
| title_short | Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro |
| title_sort | identification of anti severe acute respiratory syndrome related coronavirus 2 sars cov 2 oxysterol derivatives in vitro |
| topic | SARS-CoV-2 COVID-19 oxysterols antiviral coronavirus double membrane vesicle |
| url | https://www.mdpi.com/1422-0067/22/6/3163 |
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