J Med Virol . Inhibition of influenza A virus replication by a marine derived quinolone alkaloid targeting virus nucleoprotein

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J Med Virol


. 2023 Jan 18.
doi: 10.1002/jmv.28499. Online ahead of print.
Inhibition of influenza A virus replication by a marine derived quinolone alkaloid targeting virus nucleoprotein


Yang Zhang ¹ , Wei-Feng Xu ¹ , Yunjia Yu ¹ , Qun Zhang ^{1 2} , Lianghao Huang ¹ , Cui Hao ³ , Chang-Lun Shao ^{1 2} , Wei Wang ^{1 2}



Affiliations

• PMID: 36653877
• DOI: 10.1002/jmv.28499

Abstract

Owing to the emergence of drug resistance and high morbidity and mortality, the need for novel anti-influenza A virus (IAV) drugs with divergent targets is highly sought after. Herein, a novel quinolone alkaloid (QLA) derived from marine fungus was discovered with broad-spectrum anti-IAV activities with low toxicity. Distinct from current anti-IAV drugs, QLA may block virus replication and viral RNA (vRNA) export from the nucleus by targeting virus nucleoprotein (NP). QLA can block the binding of chromosome region maintenance 1 (CRM1) to nuclear export signal 3 (NES3) of NP to inhibit the nuclear export of NP and vRNP. QLA may also affect vRNP assembly by interfering with the binding of NP to RNA rather than NP oligomerization. Arg305 and Phe488-Gly490 may be required for the interaction between QLA and NP, and the binding pocket around these amino acids may be a promising target for anti-IAV drugs. Importantly, oral administration of QLA can protect the mice against IAV-induced death and weight loss, superior to the effects of the clinical drug oseltamivir. In summary, the marine derived compound QLA has the potential to be developed into a novel anti-IAV agent targeting virus NP protein in the future. This article is protected by copyright. All rights reserved.

Keywords: RNA binding; influenza A virus; nuclear export; nucleoprotein; quinolone alkaloid.