Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle

Yang，Fang1; Pang，Bo4; Lai，Kin Kui1; Cheung，Nam Nam1; Dai，Jun1; Zhang，Weizhe4; Zhang，Jinxia1; Chan，Kwok Hung1; Chen，Honglin1,2,3; Sze，Kong Hung1; Zhang，Hongmin6,7,8; Hao，Quan4; Yang，Dan5; Yuen，Kwok Yung1,2,3; Kao，Richard Y.1,2,3

2021-05-01

10.1128/JVI.01432-20

JOURNAL OF VIROLOGY   影响因子和分区

0022-538X

1098-5514

Influenza A viruses (IAVs) continue to pose an imminent threat to humans due to annual influenza epidemic outbreaks and episodic pandemics with high mortality rates. 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 virus infection. Here, we characterized a novel influenza A virus nucleoprotein (NP) inhibitor, FA-6005, that inhibited a broad spectrum of human pandemic and 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 potentially broad, multimechanistic anti-influenza virus therapeutic since FA-6005 suppressed influenza virus replication and perturbed intracellular trafficking of viral ribonucleoproteins (vRNPs) from early to late stages. 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 is an attractive target for drug development that inhibits multiple functions of NP. Our results also highlight 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. IMPORTANCE Current 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 lead to the emergence of antiviral drug resistance. Here, we identified a novel influenza A virus NP antagonist, FA-6005, with broad-spectrum efficacy against influenza viruses, and our study presents a comprehensive study of the mode of action of FA-6005 with the crystal structure of the compound in complex with NP. The influenza virus inhibitor holds promise as an urgently sought-after therapeutic option offering a mechanism of action complementary to existing antiviral drugs for the treatment of influenza virus infection and should further aid in the development of universal therapeutics.

Influenza Nucleoprotein Small-molecule inhibitor

SCI

英语

其他

WOS:000640382100013

MICROBIOLOGY

2-s2.0-85104276049

Scopus

1.Department of Microbiology,University of Hong Kong,Hong Kong,Hong Kong
2.Research Center of Infection and Immunology,University of Hong Kong,Hong Kong,Hong Kong
3.State Key Laboratory of Emerging Infectious Diseases,University of Hong Kong,Hong Kong,Hong Kong
4.School of Biomedical Sciences,University of Hong Kong,Hong Kong,Hong Kong
5.Department of Chemistry,University of Hong Kong,Hong Kong,Hong Kong
6.Department of Biology,Guangdong Provincial Key Laboratory of Cell Microenvironment and Disease Research,Southern University of Science and Technology,Shenzhen,China
7.Shenzhen Key Laboratory of Cell Microenvironment,Southern University of Science and Technology,Shenzhen,China
8.SUSTech-HKU Joint Laboratories for Matrix Biology and Diseases,Southern University of Science and Technology,Shenzhen,China

Yang，Fang,Pang，Bo,Lai，Kin Kui,et al. Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle[J]. JOURNAL OF VIROLOGY,2021,95(9).

Yang，Fang.,Pang，Bo.,Lai，Kin Kui.,Cheung，Nam Nam.,Dai，Jun.,...&Kao，Richard Y..(2021).Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle.JOURNAL OF VIROLOGY,95(9).

Yang，Fang,et al."Discovery of a Novel Specific Inhibitor Targeting Influenza A Virus Nucleoprotein with Pleiotropic Inhibitory Effects on Various Steps of the Viral Life Cycle".JOURNAL OF VIROLOGY 95.9(2021).