A zanamivir dimer with prophylactic and enhanced therapeutic activity against influenza viruses.
OBJECTIVE
Emerging drug resistance to antiviral therapies is an increasing challenge for the treatment of influenza virus infections. One new antiviral compound, BTA938, a dimeric derivative of the viral neuraminidase inhibitor zanamivir, contains a 14-carbon linker bridging two zanamivir moieties. In these studies, we evaluated antiviral efficacy in cell cultures infected with influenza virus and in mouse models of lethal influenza using H1N1pdm09, H3N2 and oseltamivir-resistant (H275Y) viruses.


METHODS
In vitro activity was evaluated against 22 strains of influenza virus. Additionally, in vivo studies compared the efficacy of BTA938 or zanamivir after intranasal treatment. We also tested the hypothesis of a dual mode of action for BTA938 using scanning electron microscopy (SEM).


RESULTS
BTA938 inhibited the viruses at nanomolar concentrations in vitro with a median 50% effective concentration value of 0.5 nM. In mouse models, the dimer provided ∼10-fold greater protection than zanamivir. The data also showed that a single low dose (3 mg/kg) protected 100% of mice from an otherwise lethal oseltamivir-resistant (H275Y) influenza virus infection. Remarkably, a single prophylactic treatment (10 mg/kg) administered 7 days before the challenge protected 70% of mice and when administered 1 or 3 days before the challenge it protected 90% of mice. Additionally, SEM provides evidence that the increased antiviral potency may be mediated by an enhanced aggregation of virus on the cell surface.


CONCLUSIONS
In vitro and in vivo experiments showed the high antiviral activity of BTA938 for the treatment of influenza virus infections. Moreover, we demonstrated that a single dose of BTA938 is sufficient for prophylactic and therapeutic protection in mouse models.
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA bart.tarbet@usu.edu.
E Bart
EB
Tarbet
Biota Holdings Limited, Notting Hill, Australia.
Stephanie
S
Hamilton
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Almut H
AH
Vollmer
Biota Holdings Limited, Notting Hill, Australia.
Angela
A
Luttick
Department of Microbiology and Immunology, University of Melbourne, Parkville, Australia.
Wy Ching
WC
Ng
Biota Holdings Limited, Notting Hill, Australia.
Melinda
M
Pryor
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Brett L
BL
Hurst
School of Botany, University of Melbourne, Parkville, Australia.
Simon
S
Crawford
Institute for Antiviral Research, Department of Animal, Dairy and Veterinary Sciences, Utah State University, Logan, UT, USA.
Donald F
DF
Smee
Biota Holdings Limited, Notting Hill, Australia.
Simon P
SP
Tucker
D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D004285:Dogs; D004338:Drug Combinations; D024882:Drug Resistance, Viral; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D053118:Influenza A Virus, H1N1 Subtype / Q000145:classification / Q000187:drug effects*; D053122:Influenza A Virus, H3N2 Subtype / Q000145:classification / Q000187:drug effects*; D061985:Madin Darby Canine Kidney Cells; D051379:Mice; D008807:Mice, Inbred BALB C; D009439:Neuraminidase / Q000037:antagonists & inhibitors; D009976:Orthomyxoviridae Infections / Q000188:drug therapy* / Q000821:virology; D053139:Oseltamivir / Q000494:pharmacology; D053243:Zanamivir / Q000031:analogs & derivatives* / Q000494:pharmacology*
D000998:Antiviral Agents; C000596987:BTA938; D004338:Drug Combinations; D004791:Enzyme Inhibitors; D053139:Oseltamivir; D009439:Neuraminidase; D053243:Zanamivir
neuraminidase inhibitors; oseltamivir-resistant influenza virus; prophylactic therapy