Anti-SARS-CoV-2 gapmer antisense oligonucleotides targeting the main protease region of viral RNA.

Autor: Yamasaki M; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan; Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan; Department of Applied Biological Sciences, Tokyo University of Science, Noda, 278-8510, Japan., Saso W; Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan., Yamamoto T; Infectious Diseases Unit, Tokushima Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan., Sato M; Infectious Diseases Unit, Tokushima Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan., Takagi H; Infectious Diseases Unit, Tokushima Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan., Hasegawa T; Department of Medicinal Chemistry, Tokushima Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan., Kozakura Y; Department of Drug Discovery Strategy, Office of Bioinformatics, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan., Yokoi H; Department of Drug Metabolism and Pharmacokinetics, Preclinical Research, Tokushima Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan., Ohashi H; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan., Tsuchimoto K; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan., Hashimoto R; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan., Fukushi S; Department of Virology I, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan., Uda A; Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan., Muramatsu M; Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan; Foundation for Biomedical Research and Innovation at Kobe, Institute of Biomedical Research and Innovation, Kobe, 650-0047, Japan., Takayama K; Center for iPS Cell Research and Application (CiRA), Kyoto University, Kyoto, 606-8507, Japan., Maeda K; Department of Veterinary Science, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan., Takahashi Y; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan., Nagase T; Department of Medicinal Chemistry, Tokushima Research Center for Drug Discovery, Otsuka Pharmaceutical Co., Ltd., Tokushima, 771-0192, Japan., Watashi K; Research Center for Drug and Vaccine Development, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan; Department of Virology II, National Institute of Infectious Diseases, Tokyo, 162-8640, Japan; Department of Applied Biological Sciences, Tokyo University of Science, Noda, 278-8510, Japan; MIRAI, JST, Tokyo, 102-0076, Japan. Electronic address: kwatashi@niid.go.jp.
Jazyk: angličtina
Zdroj: Antiviral research [Antiviral Res] 2024 Oct; Vol. 230, pp. 105992. Date of Electronic Publication: 2024 Aug 23.
DOI: 10.1016/j.antiviral.2024.105992
Abstrakt: Given the worldwide risk for the outbreak of emerging/re-emerging respiratory viruses, establishment of new antiviral strategies is greatly demanded. In this study, we present a scheme to identify gapmer antisense oligonucleotides (ASOs) targeting severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) RNA that efficiently inhibit viral replication. We synthesized approximately 300 gapmer ASOs designed to target various SARS-CoV-2 RNA regions and evaluated their activity in cell-based assays. Through a multistep screening in cell culture systems, we identified that ASO#41, targeting the coding region for viral main protease, reduced SARS-CoV-2 RNA levels in infected cells and inhibited virus-induced cytopathic effects. Antiviral effect of ASO#41 was also observed in iPS cell-derived human lung organoids. ASO#41 depleted intracellular viral RNAs during genome replication in an endogenous RNaseH-dependent manner. ASO#41 showed a wide range of antiviral activity against SARS-CoV-2 variants of concern including Alpha, Delta, and Omicron. Intranasal administration to mice exhibited intracellular accumulation of ASO#41 in the lung and significantly reduced the viral infectious titer, with milder body weight loss due to SARS-CoV-2 infection. Further chemical modification with phosphoryl guanidine-containing backbone linkages provided an elevation of anti-SARS-CoV-2 activity, with 23.4 nM of 50% antiviral inhibitory concentration, one of the strongest anti-SARS-CoV-2 ASOs reported so far. Our study presents an approach to identify active ASOs against SARS-CoV-2, which is potentially useful for establishing an antiviral strategy by targeting genome RNA of respiratory viruses.
Competing Interests: Declaration of competing interest TY., M.S., H.T., T.H., Y.K., H.Y., and T.N. are employees of Otsuka Pharmaceutical Co., Ltd.
(Copyright © 2024 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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