Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro
| Autor: | Kouji Kuramochi, Tadaki Suzuki, Camille Sureau, Farhad Parhami, Wakana Saso, Masamichi Muramatsu, Takaji Wakita, Chisa Kobayashi, Masako Yamasaki, Feng Wang, Kana Tsuchimoto, Michiyo Kataoka, Koichi Watashi, Makoto Takeda, Hirofumi Ohashi, Frank Stappenbeck |
|---|---|
| Rok vydání: | 2021 |
| Předmět: |
replication
Oxysterol Cell Survival Cell coronavirus Administration Oral Pharmacology medicine.disease_cause Virus Replication Antiviral Agents Catalysis Article Inorganic Chemistry lcsh:Chemistry Mice Chlorocebus aethiops polycyclic compounds medicine Animals Physical and Theoretical Chemistry Bone regeneration Molecular Biology lcsh:QH301-705.5 Vero Cells Spectroscopy Coronavirus business.industry SARS-CoV-2 Organic Chemistry COVID-19 General Medicine Oxysterols Nucleocapsid Proteins antiviral In vitro Computer Science Applications COVID-19 Drug Treatment medicine.anatomical_structure double membrane vesicle Viral replication lcsh:Biology (General) lcsh:QD1-999 Cell culture Vero cell lipids (amino acids peptides and proteins) business Viral Replication Compartments pharmacokinetics |
| Zdroj: | International Journal of Molecular Sciences International Journal of Molecular Sciences, Vol 22, Iss 3163, p 3163 (2021) Volume 22 Issue 6 |
| ISSN: | 1422-0067 |
| Popis: | 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 mM and 99% at 15 mM, respectively. When orally administered in mice, peak plasma concentrations of Oxy210 fell into a therapeutically relevant range (19 mM), 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. |
| Databáze: | OpenAIRE |
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