Potent MERS-CoV Fusion Inhibitory Peptides Identified from HR2 Domain in Spike Protein of Bat Coronavirus HKU4
Identifieur interne : 001215 ( Pmc/Curation ); précédent : 001214; suivant : 001216Potent MERS-CoV Fusion Inhibitory Peptides Identified from HR2 Domain in Spike Protein of Bat Coronavirus HKU4
Auteurs : Shuai Xia ; Qiaoshuai Lan ; Jing Pu ; Cong Wang ; Zezhong Liu ; Wei Xu ; Qian Wang ; Huan Liu [République populaire de Chine] ; Shibo Jiang [États-Unis] ; Lu LuSource :
- Viruses [ 1999-4915 ] ; 2019.
Abstract
The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and caused continual outbreaks worldwide with high mortality. However, no effective anti-MERS-CoV drug is currently available. Recently, numerous evolutionary studies have suggested that MERS-CoV originated from bat coronavirus (BatCoV). We herein reported that three peptides derived from the HR2 region in spike protein of BatCoV HKU4, including HKU4-HR2P1, HKU4-HR2P2 and HKU4-HR2P3, could bind the MERS-CoV HR1-derived peptide to form a six-helix bundle (6-HB) with high stability. Moreover, these peptides, particularly HKU4-HR2P2 and HKU4-HR2P3, exhibited potent inhibitory activity against MERS-CoV S-mediated cell–cell fusion and viral infection, suggesting that these HKU4 HR2-derived peptides could be candidates for futher development as antiviral agents against MERS-CoV infection.
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DOI: 10.3390/v11010056
PubMed: 30646495
PubMed Central: 6357153
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<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Potent MERS-CoV Fusion Inhibitory Peptides Identified from HR2 Domain in Spike Protein of Bat Coronavirus HKU4</title><author><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Lan, Qiaoshuai" sort="Lan, Qiaoshuai" uniqKey="Lan Q" first="Qiaoshuai" last="Lan">Qiaoshuai Lan</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Pu, Jing" sort="Pu, Jing" uniqKey="Pu J" first="Jing" last="Pu">Jing Pu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Cong" sort="Wang, Cong" uniqKey="Wang C" first="Cong" last="Wang">Cong Wang</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Zezhong" sort="Liu, Zezhong" uniqKey="Liu Z" first="Zezhong" last="Liu">Zezhong Liu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Xu, Wei" sort="Xu, Wei" uniqKey="Xu W" first="Wei" last="Xu">Wei Xu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Huan" sort="Liu, Huan" uniqKey="Liu H" first="Huan" last="Liu">Huan Liu</name><affiliation wicri:level="1"><nlm:aff id="af2-viruses-11-00056">State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071</wicri:regionArea></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-viruses-11-00056">Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065</wicri:regionArea></affiliation></author><author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author></titleStmt><publicationStmt><idno type="wicri:source">PMC</idno><idno type="pmid">30646495</idno><idno type="pmc">6357153</idno><idno type="url">http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6357153</idno><idno type="RBID">PMC:6357153</idno><idno type="doi">10.3390/v11010056</idno><date when="2019">2019</date><idno type="wicri:Area/Pmc/Corpus">001215</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Corpus" wicri:corpus="PMC">001215</idno><idno type="wicri:Area/Pmc/Curation">001215</idno><idno type="wicri:explorRef" wicri:stream="Pmc" wicri:step="Curation">001215</idno></publicationStmt><sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">Potent MERS-CoV Fusion Inhibitory Peptides Identified from HR2 Domain in Spike Protein of Bat Coronavirus HKU4</title><author><name sortKey="Xia, Shuai" sort="Xia, Shuai" uniqKey="Xia S" first="Shuai" last="Xia">Shuai Xia</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Lan, Qiaoshuai" sort="Lan, Qiaoshuai" uniqKey="Lan Q" first="Qiaoshuai" last="Lan">Qiaoshuai Lan</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Pu, Jing" sort="Pu, Jing" uniqKey="Pu J" first="Jing" last="Pu">Jing Pu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Cong" sort="Wang, Cong" uniqKey="Wang C" first="Cong" last="Wang">Cong Wang</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Zezhong" sort="Liu, Zezhong" uniqKey="Liu Z" first="Zezhong" last="Liu">Zezhong Liu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Xu, Wei" sort="Xu, Wei" uniqKey="Xu W" first="Wei" last="Xu">Wei Xu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Wang, Qian" sort="Wang, Qian" uniqKey="Wang Q" first="Qian" last="Wang">Qian Wang</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author><author><name sortKey="Liu, Huan" sort="Liu, Huan" uniqKey="Liu H" first="Huan" last="Liu">Huan Liu</name><affiliation wicri:level="1"><nlm:aff id="af2-viruses-11-00056">State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China</nlm:aff><country xml:lang="fr">République populaire de Chine</country><wicri:regionArea>State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071</wicri:regionArea></affiliation></author><author><name sortKey="Jiang, Shibo" sort="Jiang, Shibo" uniqKey="Jiang S" first="Shibo" last="Jiang">Shibo Jiang</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation><affiliation wicri:level="1"><nlm:aff id="af3-viruses-11-00056">Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA</nlm:aff><country xml:lang="fr">États-Unis</country><wicri:regionArea>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065</wicri:regionArea></affiliation></author><author><name sortKey="Lu, Lu" sort="Lu, Lu" uniqKey="Lu L" first="Lu" last="Lu">Lu Lu</name><affiliation><nlm:aff id="af1-viruses-11-00056">Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</nlm:aff></affiliation></author></analytic><series><title level="j">Viruses</title><idno type="eISSN">1999-4915</idno><imprint><date when="2019">2019</date></imprint></series></biblStruct></sourceDesc></fileDesc><profileDesc><textClass></textClass></profileDesc></teiHeader><front><div type="abstract" xml:lang="en"><p>The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and caused continual outbreaks worldwide with high mortality. However, no effective anti-MERS-CoV drug is currently available. Recently, numerous evolutionary studies have suggested that MERS-CoV originated from bat coronavirus (BatCoV). We herein reported that three peptides derived from the HR2 region in spike protein of BatCoV HKU4, including HKU4-HR2P1, HKU4-HR2P2 and HKU4-HR2P3, could bind the MERS-CoV HR1-derived peptide to form a six-helix bundle (6-HB) with high stability. Moreover, these peptides, particularly HKU4-HR2P2 and HKU4-HR2P3, exhibited potent inhibitory activity against MERS-CoV S-mediated cell–cell fusion and viral infection, suggesting that these HKU4 HR2-derived peptides could be candidates for futher development as antiviral agents against MERS-CoV infection.</p></div></front><back><div1 type="bibliography"><listBibl><biblStruct><analytic><author><name sortKey="Zaki, A M" uniqKey="Zaki A">A.M. 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<front><journal-meta><journal-id journal-id-type="nlm-ta">Viruses</journal-id><journal-id journal-id-type="iso-abbrev">Viruses</journal-id><journal-id journal-id-type="publisher-id">viruses</journal-id><journal-title-group><journal-title>Viruses</journal-title></journal-title-group><issn pub-type="epub">1999-4915</issn><publisher><publisher-name>MDPI</publisher-name></publisher></journal-meta><article-meta><article-id pub-id-type="pmid">30646495</article-id><article-id pub-id-type="pmc">6357153</article-id><article-id pub-id-type="doi">10.3390/v11010056</article-id><article-id pub-id-type="publisher-id">viruses-11-00056</article-id><article-categories><subj-group subj-group-type="heading"><subject>Article</subject></subj-group></article-categories><title-group><article-title>Potent MERS-CoV Fusion Inhibitory Peptides Identified from HR2 Domain in Spike Protein of Bat Coronavirus HKU4</article-title></title-group><contrib-group><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-7896-4182</contrib-id><name><surname>Xia</surname><given-names>Shuai</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0001-5524-3542</contrib-id><name><surname>Lan</surname><given-names>Qiaoshuai</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref></contrib><contrib contrib-type="author"><name><surname>Pu</surname><given-names>Jing</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Cong</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Zezhong</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref></contrib><contrib contrib-type="author"><name><surname>Xu</surname><given-names>Wei</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref></contrib><contrib contrib-type="author"><name><surname>Wang</surname><given-names>Qian</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref></contrib><contrib contrib-type="author"><name><surname>Liu</surname><given-names>Huan</given-names></name><xref ref-type="aff" rid="af2-viruses-11-00056">2</xref><xref rid="c1-viruses-11-00056" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><name><surname>Jiang</surname><given-names>Shibo</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref><xref ref-type="aff" rid="af3-viruses-11-00056">3</xref><xref rid="c1-viruses-11-00056" ref-type="corresp">*</xref></contrib><contrib contrib-type="author"><contrib-id contrib-id-type="orcid" authenticated="true">https://orcid.org/0000-0002-2255-0391</contrib-id><name><surname>Lu</surname><given-names>Lu</given-names></name><xref ref-type="aff" rid="af1-viruses-11-00056">1</xref><xref rid="c1-viruses-11-00056" ref-type="corresp">*</xref></contrib></contrib-group><aff id="af1-viruses-11-00056"><label>1</label>Key Laboratory of Medical Molecular Virology of MOE/MOH, School of Basic Medical Sciences and Shanghai Public Health Clinical Center, Fudan University, Shanghai 200032, China;<email>15111010053@fudan.edu.cn</email> (S.X.);<email>18111010010@fudan.edu.cn</email> (Q.L.);<email>17111010015@fudan.edu.cn</email> (J.P.);<email>16111010068@fudan.edu.cn</email> (C.W.);<email>17111010065@fudan.edu.cn</email> (Z.L.);<email>xuwei11@fudan.edu.cn</email> (W.X.);<email>wang_qian@fudan.edu.cn</email> (Q.W.)</aff><aff id="af2-viruses-11-00056"><label>2</label>State Key Laboratory of Virology, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430071, China</aff><aff id="af3-viruses-11-00056"><label>3</label>Lindsley F. Kimball Research Institute, New York Blood Center, New York, NY 10065, USA</aff><author-notes><corresp id="c1-viruses-11-00056"><label>*</label>Correspondence: <email>liuhuan@wh.iov.cn</email> (H.L.); <email>shibojiang@fudan.edu.cn</email> (S.J.); <email>lul@fudan.edu.cn</email> (L.L.); Tel.: +86-027-8719-9810 (H.L.); +1-212-570-3058 (S.J.); +86-21-5423-7671 (L.L.) </corresp></author-notes><pub-date pub-type="epub"><day>14</day><month>1</month><year>2019</year></pub-date><pub-date pub-type="collection"><month>1</month><year>2019</year></pub-date><volume>11</volume><issue>1</issue><elocation-id>56</elocation-id><history><date date-type="received"><day>07</day><month>12</month><year>2018</year></date><date date-type="accepted"><day>10</day><month>1</month><year>2019</year></date></history><permissions><copyright-statement>© 2019 by the authors.</copyright-statement><copyright-year>2019</copyright-year><license license-type="open-access"><license-p>Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>).</license-p></license></permissions><abstract><p>The Middle East respiratory syndrome coronavirus (MERS-CoV) emerged in 2012 and caused continual outbreaks worldwide with high mortality. However, no effective anti-MERS-CoV drug is currently available. Recently, numerous evolutionary studies have suggested that MERS-CoV originated from bat coronavirus (BatCoV). We herein reported that three peptides derived from the HR2 region in spike protein of BatCoV HKU4, including HKU4-HR2P1, HKU4-HR2P2 and HKU4-HR2P3, could bind the MERS-CoV HR1-derived peptide to form a six-helix bundle (6-HB) with high stability. Moreover, these peptides, particularly HKU4-HR2P2 and HKU4-HR2P3, exhibited potent inhibitory activity against MERS-CoV S-mediated cell–cell fusion and viral infection, suggesting that these HKU4 HR2-derived peptides could be candidates for futher development as antiviral agents against MERS-CoV infection.</p></abstract><kwd-group><kwd>MERS-CoV</kwd><kwd>fusion inhibitor</kwd><kwd>peptide</kwd><kwd>cell–cell fusion</kwd><kwd>HKU4</kwd></kwd-group></article-meta></front><floats-group><fig id="viruses-11-00056-f001" orientation="portrait" position="float"><label>Figure 1</label><caption><p>The design of HKU4 HR2-derived peptides. (<bold>A</bold>) Neighbor-joining tree created with the spike sequence of representative bat-CoVs and Infectious Bronchitis Virus (IBV). (<bold>B</bold>) The antiviral mechanism of HR2-derived peptides. (<bold>C</bold>) Schematic representation of HKU4 S protein S2 subunit. FP, fusion peptide; HR, heptad repeat domain; TM, transmembrane domain; CP, cytoplasmic domain. Corresponding sequences of the designed peptides (HKU4-HR1P and HKU4-HR2Ps) are shown in the diagram. The helical region in the HR1- and HR2-derived peptides is highlighted in the red boxes, according to the sequences of MERS-HR1P and MERS-HR2P. The identical amino acids at the <italic>e</italic> and <italic>g</italic> positions in HR1 and those at <italic>a</italic> and <italic>d</italic> positions in HR2 of MERS-CoV and HKU4 are highlighted in red. The different amino acids in HR1Ps and HR2Ps between MERS-CoV and HKU4 are highlighted in green.</p></caption><graphic xlink:href="viruses-11-00056-g001"></graphic></fig><fig id="viruses-11-00056-f002" orientation="portrait" position="float"><label>Figure 2</label><caption><p>Determination of the interactions between HKU4-HR1P with HKU4-HR2P1 (<bold>A</bold>), HKU4-HR2P2 (<bold>B</bold>) and HKU4-HR2P3 (<bold>C</bold>), as well as the interaction between MERS-HR1P with HKU4-HR2P1 (<bold>D</bold>), HKU4-HR2P2 (<bold>E</bold>) and HKU4-HR2P3 (<bold>F</bold>) by native polyacrylamide gel electrophoresis (N-PAGE).</p></caption><graphic xlink:href="viruses-11-00056-g002"></graphic></fig><fig id="viruses-11-00056-f003" orientation="portrait" position="float"><label>Figure 3</label><caption><p>Circular dichroism (CD) spectra of MERS-HR1P, MERS-HR2P and MERS-HR1P/MERS-HR2P complex (<bold>A</bold>), MERS-HR1P, HKU4-HR2P1 and MERS-HR1P/ HKU4-HR2P1 complex (<bold>B</bold>), MERS-HR1P, HKU4-HR2P2 and MERS-HR1P/ HKU4-HR2P2 complex (<bold>C</bold>), MERS-HR1P, HKU4-HR2P3 and MERS-HR1P/ HKU4-HR2P3 complex (<bold>D</bold>) in phosphate buffer (pH 7.2). (<bold>E</bold>) Melting curves of the complexes formed by MERS-HR1P and MERS-HR2P, HKU4-HR2P1, HKU4-HR2P2, or HKU4-HR2P3, respectively.</p></caption><graphic xlink:href="viruses-11-00056-g003"></graphic></fig><fig id="viruses-11-00056-f004" orientation="portrait" position="float"><label>Figure 4</label><caption><p>Inhibitory activity of peptides as demonstrated by MERS-CoV S-mediated cell–cell fusion assay. (<bold>A</bold>) Images of MERS-CoV S protein-mediated cell–cell fusion in the presence of MERS-HR1P, MERS-HR2P, HKU4-HR2P1, HKU4-HR2P2, HKU4-HR2P3 and HKU4-HR1P, respectively, all at the concentration of 10 μM. Arrows show the fused cells. Scale bars, 800 μm. (<bold>B</bold>) Inhibitory activities of MERS-HR2P, HKU4-HR2P1, HKU4-HR2P2, HKU4-HR2P3, HKU4-HR1P and MERS-HR1P against MERS-CoV S-mediated cell–cell fusion. Each sample was tested in triplicate and the data are expressed as means ± standard deviation (SD). Each experiment was repeated twice and similar results were obtained.</p></caption><graphic xlink:href="viruses-11-00056-g004"></graphic></fig><fig id="viruses-11-00056-f005" orientation="portrait" position="float"><label>Figure 5</label><caption><p>Inhibitory activity of peptides as demonstrated by pseudotyped MERS-CoV infection mediated by S protein (<bold>A</bold>) or S protein with Q1020H (<bold>B</bold>) or Q1020R (<bold>C</bold>). Each sample was tested in triplicate and the data are expressed as means ± SD. Each experiment was repeated twice and similar results were obtained.</p></caption><graphic xlink:href="viruses-11-00056-g005"></graphic></fig><table-wrap id="viruses-11-00056-t001" orientation="portrait" position="float"><object-id pub-id-type="pii">viruses-11-00056-t001_Table 1</object-id><label>Table 1</label><caption><p>Solubility and inhibitory activities of peptides.</p></caption><table frame="hsides" rules="groups"><thead><tr><th rowspan="4" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Peptide</th><th rowspan="3" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" colspan="1">Average Hydro-Philicity</th><th colspan="4" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Solubility (μM) in</th><th colspan="8" align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1">Inhibitory Activity of Peptides, IC<sub>50</sub> (μM)</th></tr><tr><th rowspan="2" colspan="2" align="center" valign="middle" style="border-bottom:solid thin">PBS (pH 7.2)</th><th rowspan="2" colspan="2" align="center" valign="middle" style="border-bottom:solid thin">Water</th><th colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Cell–Cell Fusion</th><th colspan="6" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Pseudovirus Infection</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></th><th colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Q1020</th><th colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Q1020H</th><th colspan="2" align="center" valign="middle" style="border-bottom:solid thin" rowspan="1">Q1020R</th></tr><tr><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"></th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Mean</th><th align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">SD</th></tr></thead><tbody><tr><td align="center" valign="middle" rowspan="1" colspan="1">HKU4-HR2P1</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0</td><td align="center" valign="middle" rowspan="1" colspan="1">1569</td><td align="center" valign="middle" rowspan="1" colspan="1">110</td><td align="center" valign="middle" rowspan="1" colspan="1">651</td><td align="center" valign="middle" rowspan="1" colspan="1">40</td><td align="center" valign="middle" rowspan="1" colspan="1">1.09</td><td align="center" valign="middle" rowspan="1" colspan="1">0.21</td><td align="center" valign="middle" rowspan="1" colspan="1">2.15</td><td align="center" valign="middle" rowspan="1" colspan="1">0.17</td><td align="center" valign="middle" rowspan="1" colspan="1">2.72</td><td align="center" valign="middle" rowspan="1" colspan="1">0.59</td><td align="center" valign="middle" rowspan="1" colspan="1">2.42</td><td align="center" valign="middle" rowspan="1" colspan="1">0.93</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">HKU4-HR2P2</td><td align="center" valign="middle" rowspan="1" colspan="1">0.2</td><td align="center" valign="middle" rowspan="1" colspan="1">2924</td><td align="center" valign="middle" rowspan="1" colspan="1">131</td><td align="center" valign="middle" rowspan="1" colspan="1">150</td><td align="center" valign="middle" rowspan="1" colspan="1">25</td><td align="center" valign="middle" rowspan="1" colspan="1">0.38</td><td align="center" valign="middle" rowspan="1" colspan="1">0.01</td><td align="center" valign="middle" rowspan="1" colspan="1">0.34</td><td align="center" valign="middle" rowspan="1" colspan="1">0.06</td><td align="center" valign="middle" rowspan="1" colspan="1">0.44</td><td align="center" valign="middle" rowspan="1" colspan="1">0.1</td><td align="center" valign="middle" rowspan="1" colspan="1">0.3</td><td align="center" valign="middle" rowspan="1" colspan="1">0.04</td></tr><tr><td align="center" valign="middle" rowspan="1" colspan="1">HKU4-HR2P3</td><td align="center" valign="middle" rowspan="1" colspan="1">0.0</td><td align="center" valign="middle" rowspan="1" colspan="1">118</td><td align="center" valign="middle" rowspan="1" colspan="1">13</td><td align="center" valign="middle" rowspan="1" colspan="1">1674</td><td align="center" valign="middle" rowspan="1" colspan="1">73</td><td align="center" valign="middle" rowspan="1" colspan="1">0.55</td><td align="center" valign="middle" rowspan="1" colspan="1">0.06</td><td align="center" valign="middle" rowspan="1" colspan="1">0.48</td><td align="center" valign="middle" rowspan="1" colspan="1">0.08</td><td align="center" valign="middle" rowspan="1" colspan="1">0.52</td><td align="center" valign="middle" rowspan="1" colspan="1">0.1</td><td align="center" valign="middle" rowspan="1" colspan="1">0.4</td><td align="center" valign="middle" rowspan="1" colspan="1">0.03</td></tr><tr><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">MERS-HR2P</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">−0.2</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">105</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">12</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">29</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">14</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.07</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.22</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.14</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.02</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.71</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.02</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">1.31</td><td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">0.07</td></tr></tbody></table><table-wrap-foot><fn><p>IC<sub>50</sub>: Concentration of peptide at which 50% of HCoV S-mediated cell–cell fusion was blocked.</p></fn></table-wrap-foot></table-wrap></floats-group></pmc></record>Pour manipuler ce document sous Unix (Dilib)
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