Abstract
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.
Highlights
Seasonal influenza epidemics lead to 3–5 million severe infections and 290,000–650,000 annual global deaths
An analogous binding study was performed on virus-infected normal human bronchial epithelial (NHBE) cells grown at air–liquid interface (ALI)
With data documenting that individuals receiving an influenza vaccine can still contract infections from viral strains contained in the vaccine[29], together with studies showing that neuraminidase inhibitors can only mitigate an influenza infection when administered early during the infection process[6], the potent eradication by zanamivir-DNP conjugate (zan-DNP) of advanced infections involving very high viral loads was not anticipated
Summary
Seasonal influenza epidemics lead to 3–5 million severe infections and 290,000–650,000 annual global deaths. We design and synthesize a bifunctional small molecule by conjugating the neuraminidase inhibitor, zanamivir, with the highly immunogenic hapten, dinitrophenyl (DNP), which 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. We show that zan-DNP inhibits neuraminidases of both influenza A and B viruses and concurrently recruits anti-DNP antibodies to virus-infected cells Because this anti-DNP binding mediates destruction of the opsonized virus and virus-infected cells, treatment with zan-DNP is observed to eradicate even the severe viral infections where mice are inoculated with 100× MLD50 of viral load and therapy is not initiated until 3 days postinfection. Considering that a single intranasal or intraperitoneal dose of zan-DNP yields a complete response, we suggest that further development of zan-DNP as a universal anti-influenza therapy is warranted
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
