Identification of a novel compound targeting the nuclear export of influenza A virus nucleoprotein |
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| Authors: | Feng Huang Jingliang Chen Junsong Zhang Likai Tan Gui Lu Yongjie Luo Ting Pan Juanran Liang Qianwen Li Baohong Luo Hui Zhang Gen Lu |
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| Affiliation: | 1. Department of Respiration, Affiliated Guangzhou Women and Children's Hospital, Zhongshan School of Medicine, Sun Yat‐Sen University, Guangzhou, China;2. Institute of Human Virology, Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, China;3. Key Laboratory of Tropical Disease Control of Ministry of Education, Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, China;4. Guangdong Engineering Research Center for Antimicrobial Agent and Immunotechnology, Zhongshan School of Medicine, Sun Yat‐sen University, Guangzhou, China;5. Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Sun Yat‐sen University, Guangzhou, China |
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| Abstract: | Although antiviral drugs are available for the treatment of influenza infection, it is an urgent requirement to develop new antiviral drugs regarding the emergence of drug‐resistant viruses. The nucleoprotein (NP) is conserved among all influenza A viruses (IAVs) and has no cellular equivalent. Therefore, NP is an ideal target for the development of new IAV inhibitors. In this study, we identified a novel anti‐influenza compound, ZBMD‐1, from a library of 20,000 compounds using cell‐based influenza A infection assays. We found that ZBMD‐1 inhibited the replication of H1N1 and H3N2 influenza A virus strains in vitro, with an IC50 ranging from 0.41–1.14 μM. Furthermore, ZBMD‐1 inhibited the polymerase activity and specifically impaired the nuclear export of NP. Further investigation indicated that ZBMD‐1 binds to the nuclear export signal 3 (NES3) domain and the dimer interface of the NP pocket. ZBMD‐1 also protected mice that were challenged with lethal doses of A/PR/8/1934 (H1N1) virus, effectively relieving lung histopathology changes, as well as strongly inhibiting the expression of pro‐inflammatory cytokines/chemokines, without inducing toxicity effects in mice. These results suggest that ZBMD‐1 is a promising anti‐influenza compound which can be further investigated as a useful strategy against IAVs in the future. |
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| Keywords: | influenza A virus compound ZBMD‐1 nucleoprotein nuclear export |
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