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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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Autores principales: 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
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
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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.
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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
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