G-quadruplex-forming small RNA inhibits coronavirus and influenza A virus replication

Ryoya Sekine; Kouki Takeda; Tsukasa Suenaga; Satsuki Tsuno; Takumi Kaiya; Maki Kiso; Seiya Yamayoshi; Yoshihide Takaku; Shiho Ohno; Yoshiki Yamaguchi; Seiichi Nishizawa; Kazuhiro Sumitomo; Kazufumi Ikuta; Teru Kanda; Yoshihiro Kawaoka; Hidekazu Nishimura; Shusuke Kuge

doi:10.1038/s42003-024-07351-7

G-quadruplex-forming small RNA inhibits coronavirus and influenza A virus replication

Commun Biol. 2025 Jan 15;8(1):27. doi: 10.1038/s42003-024-07351-7.

Authors

Ryoya Sekine^#¹, Kouki Takeda¹, Tsukasa Suenaga¹, Satsuki Tsuno¹, Takumi Kaiya¹, Maki Kiso^{2

3}, Seiya Yamayoshi^{2

3

4}, Yoshihide Takaku⁵, Shiho Ohno⁶, Yoshiki Yamaguchi⁶, Seiichi Nishizawa⁵, Kazuhiro Sumitomo⁷, Kazufumi Ikuta⁸, Teru Kanda⁸, Yoshihiro Kawaoka^{2

3

4}, Hidekazu Nishimura⁹, Shusuke Kuge^#¹⁰

Affiliations

¹ Division of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsuhima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan.
² Division of Virology, Institute of Medical Sciences, The University of Tokyo, 4-6-1 Shiroganedai, Minato-ku, Tokyo, 108-8639, Japan.
³ The University of Tokyo, Pandemic Preparedness, Infection, and Advanced Research Center, Tokyo, Japan.
⁴ The Research Center for Global Viral Diseases, National Center for Global Health and Medicine Research Institute, Tokyo, Japan.
⁵ Department of Chemistry, Graduate School of Science, Tohoku University, 6-3 Azaaoba, Aoba-ku, Sendai, Miyagi, 980-8578, Japan.
⁶ Division of Structural Glycobiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsuhima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan.
⁷ Division of Geriatric and Community Medicine, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino-ku, Sendai, Miyagi, 983-8536, Japan.
⁸ Division of Microbiology, Faculty of Medicine, Tohoku Medical and Pharmaceutical University, 1-15-1, Fukumuro, Miyagino-ku, Sendai, Miyagi, 983-8536, Japan.
⁹ Virus Research Center, Clinical Research Division, National Hospital Organization Sendai Medical Center, 2-1-12, Miyagino, Miyagino-ku, Sendai, Miyagi, 983-8520, Japan.
¹⁰ Division of Microbiology, Faculty of Pharmaceutical Sciences, Tohoku Medical and Pharmaceutical University, 4-4-1, Komatsuhima, Aoba-ku, Sendai, Miyagi, 981-8558, Japan. skuge@tohoku-mpu.ac.jp.

^# Contributed equally.

PMID: 39815031
DOI: 10.1038/s42003-024-07351-7

Abstract

Future pandemic threats may be caused by novel coronaviruses and influenza A viruses. Here we show that when directly added to a cell culture, 12mer guanine RNA (G12) and its phosphorothioate-linked derivatives (G12(S)), rapidly entered cytoplasm and suppressed the propagation of human coronaviruses and influenza A viruses to between 1/100 and nearly 1/1000 of normal virus infectivity without cellular toxicity and induction of innate immunity. Moreover, G12(S) alleviated the weight loss caused by coronavirus infection in mice. G12(S) might exhibit a stable G-tetrad with left-handed parallel-stranded G-quadruplex, and inhibit the replication process by impeding interaction between viral nucleoproteins and viral RNA in the cytoplasm. Unlike previous antiviral strategies that target the G-quadruplexes of the viral genome, we now show that excess exogenous G-quadruplex-forming small RNA displaces genomic RNA from ribonucleoprotein, effectively inhibiting viral replication. The approach has the potential to facilitate the creation of versatile middle-molecule antivirals featuring lipid nanoparticle-free delivery.

Abstract

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