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

International Journal of Molecular Sciences

Kouji Kuramochi¹  Tadaki Suzuki²  Michiyo Kataoka²  Wakana Saso³  Kana Tsuchimoto³  Koichi Watashi³  Masako Yamasaki³  Chisa Kobayashi³  Masamichi Muramatsu³  Hirofumi Ohashi³  Takaji Wakita³  Makoto Takeda⁴  Camille Sureau⁵  Feng Wang⁶  Farhad Parhami⁶  Frank Stappenbeck⁶ 

[1] Department of Applied Biological Sciences, Tokyo University of Science, Noda 278-8510, Japan;Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;Department of Virology II, National Institute of Infectious Diseases, Tokyo 162-8640, Japan;Department of Virology III, National Institute of Infectious Diseases, Tokyo 208-0011, Japan;Laboratoire de Virologie Moléculaire, Institut National de la Transfusion Sanguine, 75739 Paris, France;MAX BioPharma, Inc., 2870 Colorado Avenue, Santa Monica, CA 90404, USA;

关键词: SARS-CoV-2;    COVID-19;    oxysterols;    antiviral;    coronavirus;    double membrane vesicle;   

DOI  :  10.3390/ijms22063163

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown