TY - JOUR
T1 - A universal dual mechanism immunotherapy for the treatment of influenza virus infections
AU - Liu, Xin
AU - Zhang, Boning
AU - Wang, Yingcai
AU - Haymour, Hanan S.
AU - Zhang, Fenghua
AU - Xu, Le cun
AU - Srinivasarao, Madduri
AU - Low, Philip S.
N1 - Funding Information:
We thank BEI Resources, NIAID, NIH for providing the influenza viruses used in this study. This research was supported by Endocyte Inc. (Endocyte Grant#: 201194).
Publisher Copyright:
© 2020, The Author(s).
PY - 2020/12/1
Y1 - 2020/12/1
N2 - Seasonal influenza epidemics lead to 3–5 million severe infections and 290,000–650,000 annual global deaths. With deaths from the 1918 influenza pandemic estimated at >50,000,000 and future pandemics anticipated, the need for a potent influenza treatment is critical. In this study, we design and synthesize a bifunctional small molecule by conjugating the neuraminidase inhibitor, zanamivir, with the highly immunogenic hapten, dinitrophenyl (DNP), which specifically targets the surface of free virus and viral-infected cells. We show that this leads to simultaneous inhibition of virus release, and immune-mediated elimination of both free virus and virus-infected cells. Intranasal or intraperitoneal administration of a single dose of drug to mice infected with 100x MLD50 virus is shown to eradicate advanced infections from representative strains of both influenza A and B viruses. Since treatments of severe infections remain effective up to three days post lethal inoculation, our approach may successfully treat infections refractory to current therapies.
AB - Seasonal influenza epidemics lead to 3–5 million severe infections and 290,000–650,000 annual global deaths. With deaths from the 1918 influenza pandemic estimated at >50,000,000 and future pandemics anticipated, the need for a potent influenza treatment is critical. In this study, we design and synthesize a bifunctional small molecule by conjugating the neuraminidase inhibitor, zanamivir, with the highly immunogenic hapten, dinitrophenyl (DNP), which specifically targets the surface of free virus and viral-infected cells. We show that this leads to simultaneous inhibition of virus release, and immune-mediated elimination of both free virus and virus-infected cells. Intranasal or intraperitoneal administration of a single dose of drug to mice infected with 100x MLD50 virus is shown to eradicate advanced infections from representative strains of both influenza A and B viruses. Since treatments of severe infections remain effective up to three days post lethal inoculation, our approach may successfully treat infections refractory to current therapies.
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U2 - 10.1038/s41467-020-19386-5
DO - 10.1038/s41467-020-19386-5
M3 - Article
C2 - 33154358
AN - SCOPUS:85095432953
VL - 11
JO - Nat Commun
JF - Nat Commun
SN - 2041-1723
IS - 1
M1 - 5597
ER -