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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.
  • Ohashi H; Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Wang F; Department of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, Japan.
  • Stappenbeck F; MAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USA.
  • Tsuchimoto K; MAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USA.
  • Kobayashi C; Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Saso W; Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Kataoka M; Department of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, Japan.
  • Yamasaki M; Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Kuramochi K; The Institute of Medical Science, The University of Tokyo, Tokyo 108-8639, Japan.
  • Muramatsu M; AIDS Research Center, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Suzuki T; Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Sureau C; Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Takeda M; Department of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, Japan.
  • Wakita T; Department of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, Japan.
  • Parhami F; Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
  • Watashi K; Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
Int J Mol Sci ; 22(6)2021 Mar 19.
Article in English | MEDLINE | ID: covidwho-1143519
Preprint
This scientific journal article is probably based on a previously available preprint. It has been identified through a machine matching algorithm, human confirmation is still pending.
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Semantic information from SemMedBD (by NLM)
1. Antiviral Agents TREATS 2019 novel coronavirus
Subject
Antiviral Agents
Predicate
TREATS
Object
2019 novel coronavirus
2. cholesterol DISRUPTS Malignant Neoplasms
Subject
cholesterol
Predicate
DISRUPTS
Object
Malignant Neoplasms
3. Cultured Cell Line LOCATION_OF Hydroxycholesterols
Subject
Cultured Cell Line
Predicate
LOCATION_OF
Object
Hydroxycholesterols
4. Cultured Cell Line LOCATION_OF 27-hydroxycholesterol
Subject
Cultured Cell Line
Predicate
LOCATION_OF
Object
27-hydroxycholesterol
5. Oxysterols DISRUPTS Virus Replication
Subject
Oxysterols
Predicate
DISRUPTS
Object
Virus Replication
6. Virus Replication AFFECTS Anabolism
Subject
Virus Replication
Predicate
AFFECTS
Object
Anabolism
7. Increased risk PROCESS_OF Vulnerable Populations
Subject
Increased risk
Predicate
PROCESS_OF
Object
Vulnerable Populations
8. Antiviral Agents TREATS 2019 novel coronavirus
Subject
Antiviral Agents
Predicate
TREATS
Object
2019 novel coronavirus
9. cholesterol DISRUPTS Malignant Neoplasms
Subject
cholesterol
Predicate
DISRUPTS
Object
Malignant Neoplasms
10. Cultured Cell Line LOCATION_OF Hydroxycholesterols
Subject
Cultured Cell Line
Predicate
LOCATION_OF
Object
Hydroxycholesterols
11. Cultured Cell Line LOCATION_OF 27-hydroxycholesterol
Subject
Cultured Cell Line
Predicate
LOCATION_OF
Object
27-hydroxycholesterol
12. Oxysterols DISRUPTS Virus Replication
Subject
Oxysterols
Predicate
DISRUPTS
Object
Virus Replication
13. Virus Replication AFFECTS Anabolism
Subject
Virus Replication
Predicate
AFFECTS
Object
Anabolism
14. Increased risk PROCESS_OF Vulnerable Populations
Subject
Increased risk
Predicate
PROCESS_OF
Object
Vulnerable Populations
ABSTRACT
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.
Subject(s)
Keywords

Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Oxysterols / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study Limits: Animals Language: English Year: 2021 Document Type: Article Affiliation country: Ijms22063163

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Oxysterols / SARS-CoV-2 Type of study: Diagnostic study / Prognostic study Limits: Animals Language: English Year: 2021 Document Type: Article Affiliation country: Ijms22063163