Identification of Anti-Severe Acute Respiratory Syndrome-Related Coronavirus 2 (SARS-CoV-2) Oxysterol Derivatives In Vitro.

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.

• Authors: 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
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 22 Issue 6 (Mar 19 2021) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33808940 (Publication Type: Journal Article)

Chemical References

• Antiviral Agents
• Nucleocapsid Proteins
• Oxysterols

Topics

• Administration, Oral
• Animals
• Antiviral Agents (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• Cell Survival (drug effects)
• Chlorocebus aethiops
• Mice
• Nucleocapsid Proteins (drug effects)
• Oxysterols (administration & dosage, chemistry, pharmacokinetics, pharmacology)
• SARS-CoV-2 (drug effects, genetics)
• Vero Cells
• Viral Replication Compartments (drug effects)
• Virus Replication (drug effects)
• COVID-19 Drug Treatment