J Virol . Discovery of a novel specific inhibitor targeting influenza A nucleoprotein with pleiotropic inhibitory effects on various steps of viral life cycle

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J Virol


. 2021 Feb 24;JVI.01432-20.
doi: 10.1128/JVI.01432-20. Online ahead of print.
Discovery of a novel specific inhibitor targeting influenza A nucleoprotein with pleiotropic inhibitory effects on various steps of viral life cycle


Fang Yang ¹ , Bo Pang ² , Kin Kui Lai ¹ , Nam Nam Cheung ¹ , Jun Dai ¹ , Weizhe Zhang ² , Jinxia Zhang ¹ , Kwok-**** Chan ¹ , Honglin Chen ^{1 3 4} , Kong-**** Sze ¹ , Hongmin Zhang ⁵ , Quan Hao ² , Dan Yang ⁶ , Kwok-Yung Yuen ^{7 3 4} , Richard Y Kao ^{7 3 4}



Affiliations

• PMID: 33627391
• DOI: 10.1128/JVI.01432-20

Free article

Abstract

Influenza viruses (IAV) continue to pose an imminent threat to human due to annual influenza epidemics outbreak and episodic pandemics with high mortality. In this context, the suboptimal vaccine coverage and efficacy, coupled with recurrent events of viral resistance against a very limited antiviral portfolio, emphasize an urgent need for new additional prophylactic and therapeutic options, including new antiviral targets and drugs with new mechanisms of action to prevent and treat influenza infection. Here we characterized a novel influenza A nucleoprotein (NP) inhibitor FA-6005 that inhibited a broad spectrum of human pandemic, seasonal influenza A and B viruses in vitro and protects mice against lethal influenza A virus challenge. The small molecule FA-6005 targeted a conserved NP I41 domain and acted as a potential broad, multi-mechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNP) from early to late stage. Cocrystal structures of the NP/FA-6005 complex reconciled well with concurrent mutational studies. This study provides the first line of direct evidence suggesting that the newly-identified NP I41 pocket as an attractive target for drug development that inhibit the multiple functions of NP. Our results also highlighted FA-6005 as a promising candidate for further development as an antiviral drug for the treatment of IAV infection and provide chemical-level details for inhibitor optimization.ImportanceCurrent influenza antivirals have limitations with regard to their effectiveness and the potential emergence of resistance. Therefore, there is an urgent need for broad-spectrum inhibitors to address the considerable challenges posed by the rapid evolution of influenza viruses that limit the effectiveness of vaccines and the emergence of antiviral drug resistance. Herein we identified a novel influenza A virus NP antagonist FA-6005 with broad-spectrum efficacy against influenza viruses and our study presented a comprehensive study of mode of action of FA-6005 with the crystal structure of the compound in complex with NP. The influenza inhibitor holds promise as an urgently sought-after therapeutic option offering a complementary mechanism of action to existing antiviral drugs for the treatment of influenza virus infection, and that should further aid development of universal therapeutics.