Abstract
Viruses possessing class I fusion proteins require proteolytic activation by host cell proteases to mediate fusion with the host cell membrane. The mammalian SPINT2 gene encodes a protease inhibitor that targets trypsin-like serine proteases. Here we show the protease inhibitor, SPINT2, restricts cleavage-activation efficiently for a range of influenza viruses and for human metapneumovirus (HMPV). SPINT2 treatment resulted in the cleavage and fusion inhibition of full-length influenza A/CA/04/09 (H1N1) HA, A/Aichi/68 (H3N2) HA, A/Shanghai/2/2013 (H7N9) HA and HMPV F when activated by trypsin, recombinant matriptase or KLK5. We also demonstrate that SPINT2 was able to reduce viral growth of influenza A/CA/04/09 H1N1 and A/X31 H3N2 in cell culture by inhibiting matriptase or TMPRSS2. Moreover, inhibition efficacy did not differ whether SPINT2 was added at the time of infection or 24 h post-infection. Our data suggest that the SPINT2 inhibitor has a strong potential to serve as a novel broad-spectrum antiviral.
Keywords:
Antiviral therapy; HAI-2; HMPV; HMPV F; Hemagglutinin; Influenza; Proteases; SPINT2.
Copyright © 2020 Elsevier Inc. All rights reserved.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Cell Line
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Cell Survival / drug effects
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Hemagglutinin Glycoproteins, Influenza Virus / metabolism
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Host-Pathogen Interactions
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Humans
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Influenza A Virus, H1N1 Subtype / drug effects
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Influenza A Virus, H1N1 Subtype / growth & development
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Influenza A Virus, H1N1 Subtype / metabolism
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Influenza A Virus, H1N1 Subtype / physiology
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Influenza A Virus, H3N2 Subtype / drug effects
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Influenza A Virus, H3N2 Subtype / growth & development
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Influenza A Virus, H3N2 Subtype / metabolism
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Influenza A Virus, H3N2 Subtype / physiology
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Influenza A Virus, H7N9 Subtype / drug effects
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Influenza A Virus, H7N9 Subtype / growth & development
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Influenza A Virus, H7N9 Subtype / metabolism
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Influenza A Virus, H7N9 Subtype / physiology
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Influenza A virus / drug effects*
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Influenza A virus / growth & development
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Influenza A virus / metabolism
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Influenza A virus / physiology
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Membrane Glycoproteins / genetics
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Membrane Glycoproteins / metabolism*
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Membrane Glycoproteins / pharmacology*
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Metapneumovirus / drug effects*
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Metapneumovirus / growth & development
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Metapneumovirus / metabolism
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Metapneumovirus / physiology
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Peptide Hydrolases / metabolism
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Protease Inhibitors / pharmacology
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Recombinant Proteins / pharmacology
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Serine Endopeptidases / metabolism
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Serine Proteinase Inhibitors / metabolism
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Serine Proteinase Inhibitors / pharmacology*
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Trypsin Inhibitors / metabolism
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Trypsin Inhibitors / pharmacology
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Viral Fusion Proteins / metabolism*
Substances
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Hemagglutinin Glycoproteins, Influenza Virus
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Membrane Glycoproteins
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Protease Inhibitors
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Recombinant Proteins
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SPINT2 protein, human
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Serine Proteinase Inhibitors
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Trypsin Inhibitors
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Viral Fusion Proteins
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Peptide Hydrolases
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Serine Endopeptidases
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TMPRSS2 protein, human