Development of ciclesonide analogues that block SARS-CoV-2 RNA replication

Genichiro Tsuji; Kenzo Yonemitsu; Takahito Ito; Yuta Yanase; Masashi Uema; Nobumichi Ohoka; Takao Inoue; Hiroshi Asakura; Yosuke Demizu

doi:10.1016/j.bmcl.2021.128052

Development of ciclesonide analogues that block SARS-CoV-2 RNA replication

Bioorg Med Chem Lett. 2021 Jul 1:43:128052. doi: 10.1016/j.bmcl.2021.128052. Epub 2021 Apr 20.

Authors

Genichiro Tsuji¹, Kenzo Yonemitsu², Takahito Ito¹, Yuta Yanase³, Masashi Uema², Nobumichi Ohoka⁴, Takao Inoue⁴, Hiroshi Asakura², Yosuke Demizu⁵

Affiliations

¹ Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
² Division of Biomedical Food Research, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
³ Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa 230-0045, Japan.
⁴ Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan.
⁵ Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Tonomachi, Kawasaki, Kanagawa 210-9501, Japan; Graduate School of Medical Life Science, Yokohama City University, 1-7-29, Yokohama, Kanagawa 230-0045, Japan. Electronic address: demizu@nihs.go.jp.

Abstract

Ciclesonide is an inhaled corticosteroid used to treat asthma and is currently undergoing clinical trials for treatment of coronavirus disease 2019 (COVID-19). An active metabolite of ciclesonide, Cic2, was recently reported to repress severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genomic RNA replication. Herein, we designed and synthesized a few types of ciclesonide analogues. Cic4 (bearing an azide group) and Cic6 (bearing a chloro group) potently decreased SARS-CoV-2 viral replication and had low cytotoxicity compared with Cic2 (bearing a hydroxy group). These compounds are promising as novel therapeutic agents for COVID-19 that show significant antiviral activity.

Keywords: COVID-19; Ciclesonide; Endonuclease; SARS-CoV-2; Viral growth inhibition.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

COVID-19 / virology
COVID-19 Drug Treatment*
Glucocorticoids / pharmacology
Humans
Pregnenediones / pharmacology*
RNA, Viral / antagonists & inhibitors*
RNA, Viral / genetics
SARS-CoV-2 / drug effects*
SARS-CoV-2 / genetics
Virus Replication / genetics

Substances

Glucocorticoids
Pregnenediones
RNA, Viral
ciclesonide