Cargando…
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...
Autores principales: | , , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2021
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003796/ https://www.ncbi.nlm.nih.gov/pubmed/33808940 http://dx.doi.org/10.3390/ijms22063163 |
_version_ | 1783671773705797632 |
---|---|
author | Ohashi, Hirofumi Wang, Feng Stappenbeck, Frank Tsuchimoto, Kana Kobayashi, Chisa Saso, Wakana Kataoka, Michiyo Yamasaki, Masako Kuramochi, Kouji Muramatsu, Masamichi Suzuki, Tadaki Sureau, Camille Takeda, Makoto Wakita, Takaji Parhami, Farhad Watashi, Koichi |
author_facet | Ohashi, Hirofumi Wang, Feng Stappenbeck, Frank Tsuchimoto, Kana Kobayashi, Chisa Saso, Wakana Kataoka, Michiyo Yamasaki, Masako Kuramochi, Kouji Muramatsu, Masamichi Suzuki, Tadaki Sureau, Camille Takeda, Makoto Wakita, Takaji Parhami, Farhad Watashi, Koichi |
author_sort | Ohashi, Hirofumi |
collection | PubMed |
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(R)-hydroxycholesterol, 24(S)-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. |
format | Online Article Text |
id | pubmed-8003796 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-80037962021-03-28 Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro Ohashi, Hirofumi Wang, Feng Stappenbeck, Frank Tsuchimoto, Kana Kobayashi, Chisa Saso, Wakana Kataoka, Michiyo Yamasaki, Masako Kuramochi, Kouji Muramatsu, Masamichi Suzuki, Tadaki Sureau, Camille Takeda, Makoto Wakita, Takaji Parhami, Farhad Watashi, Koichi Int J Mol Sci Article 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(R)-hydroxycholesterol, 24(S)-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. MDPI 2021-03-19 /pmc/articles/PMC8003796/ /pubmed/33808940 http://dx.doi.org/10.3390/ijms22063163 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article Ohashi, Hirofumi Wang, Feng Stappenbeck, Frank Tsuchimoto, Kana Kobayashi, Chisa Saso, Wakana Kataoka, Michiyo Yamasaki, Masako Kuramochi, Kouji Muramatsu, Masamichi Suzuki, Tadaki Sureau, Camille Takeda, Makoto Wakita, Takaji Parhami, Farhad Watashi, Koichi Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro |
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 | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8003796/ https://www.ncbi.nlm.nih.gov/pubmed/33808940 http://dx.doi.org/10.3390/ijms22063163 |
work_keys_str_mv | AT ohashihirofumi identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT wangfeng identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT stappenbeckfrank identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT tsuchimotokana identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT kobayashichisa identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT sasowakana identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT kataokamichiyo identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT yamasakimasako identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT kuramochikouji identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT muramatsumasamichi identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT suzukitadaki identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT sureaucamille identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT takedamakoto identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT wakitatakaji identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT parhamifarhad identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro AT watashikoichi identificationofantisevereacuterespiratorysyndromerelatedcoronavirus2sarscov2oxysterolderivativesinvitro |