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.
| Original language | English (US) |
|---|---|
| Article number | 5597 |
| Pages (from-to) | 5597 |
| Journal | Nature Communications |
| Volume | 11 |
| Issue number | 1 |
| DOIs | |
| State | Published - Nov 5 2020 |
Keywords
- 2,4-Dinitrophenol/administration & dosage
- Administration, Intranasal
- Animals
- Antibodies/administration & dosage
- Antiviral Agents/administration & dosage
- Cell Line
- Cytotoxicity, Immunologic/drug effects
- Drug Delivery Systems
- Humans
- Immunotherapy/methods
- Influenza A virus/drug effects
- Influenza B virus/drug effects
- Infusions, Parenteral
- Mice
- Mice, Inbred BALB C
- Neuraminidase/antagonists & inhibitors
- Orthomyxoviridae Infections/drug therapy
- Protein Binding
- Treatment Outcome
- Virus Release/drug effects
- Zanamivir/administration & dosage
ASJC Scopus subject areas
- Physics and Astronomy(all)
- Chemistry(all)
- Biochemistry, Genetics and Molecular Biology(all)