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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,10,18]]},"abstract":"<jats:p>Influenza virus neuraminidase (NA) is an important target for antiviral development because it plays a crucial role in releasing newly assembled viruses. Two unique influenza-like virus genomes were recently reported in the Wuhan Asiatic toad and Wuhan spiny eel. Their NA genes appear to be highly divergent from all known influenza NAs, raising key questions as to whether the Asiatic toad influenza-like virus NA (tNA) and spiny eel NA (eNA) have canonical NA activities and structures and whether they show sensitivity to NA inhibitors (NAIs). Here, we found that both tNA and eNA have neuraminidase activities. A detailed structural analysis revealed that tNA and eNA present similar overall structures to currently known NAs, with a conserved calcium binding site. Inhibition assays indicated that tNA is resistant to NAIs, while eNA is still sensitive to NAIs. E119 is conserved in canonical NAs. The P119E substitution in tNA can restore sensitivity to NAIs, and, in contrast, the E119P substitution in eNA decreased its sensitivity to NAIs. The structures of NA\u2013inhibitor complexes further provide a detailed insight into NA\u2013inhibitor interactions at the atomic level. Moreover, tNA and eNA have unique N-glycosylation sites compared with canonical NAs. Collectively, the structural features, NA activities, and sensitivities to NAIs suggest that fish- and amphibian-derived influenza-like viruses may circulate in these vertebrates. More attention should be paid to these influenza-like viruses because their NA molecules may play roles in the emergence of NAI resistance.<\/jats:p>","DOI":"10.1073\/pnas.2210724119","type":"journal-article","created":{"date-parts":[[2022,10,3]],"date-time":"2022-10-03T15:17:45Z","timestamp":1664810265000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":5,"title":["Structural and inhibitor sensitivity analysis of influenza B\u2013like viral neuraminidases derived from Asiatic toad and spiny eel"],"prefix":"10.1073","volume":"119","author":[{"given":"Linghui","family":"Li","sequence":"first","affiliation":[{"name":"CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"},{"name":"Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yan","family":"Chai","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Weiyu","family":"Peng","sequence":"additional","affiliation":[{"name":"College of Veterinary Medicine, China Agricultural University, Beijing 100193, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Delin","family":"Li","sequence":"additional","affiliation":[{"name":"Shanxi Academy of Advanced Research and Innovation, Taiyuan 030032, China"},{"name":"Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8415-989X","authenticated-orcid":false,"given":"Litao","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Public Health (Shenzhen), Sun Yat-Sen University, Guangzhou 510080, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3869-615X","authenticated-orcid":false,"given":"George Fu","family":"Gao","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China"},{"name":"University of Chinese Academy of Sciences, Beijing 100049, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9358-4732","authenticated-orcid":false,"given":"Jianxun","family":"Qi","sequence":"additional","affiliation":[{"name":"CAS Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences (CAS), Beijing 100101, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haixia","family":"Xiao","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William Jun","family":"Liu","sequence":"additional","affiliation":[{"name":"National Health Commission (NHC) Laboratory of Biosafety, National Institute for Viral Disease Control and Prevention, Chinese Center for Disease Control and Prevention (China CDC), Beijing 102206, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6302-7524","authenticated-orcid":false,"given":"Mark","family":"von Itzstein","sequence":"additional","affiliation":[{"name":"Institute for Glycomics, Griffith University, Southport, QLD 4222, Australia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0670-010X","authenticated-orcid":false,"given":"Feng","family":"Gao","sequence":"additional","affiliation":[{"name":"Laboratory of Protein Engineering and Vaccines, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"},{"name":"Laboratory of Structural Biology, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin 300308, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,10,3]]},"reference":[{"key":"e_1_3_4_1_2","volume-title":"Fields Virology","author":"Knipe D. 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