Here we present data on a first in kind antiviral against influenza, a product of Aus Bio Ltd, which has a modular structure and a dual mode of action. This compound possesses an effector domain that creates an acidic microenvironment mimicking the low pH found inside the endosome. This domain induces the irreversible pH dependant conformational change in the haemagglutinin and prevents attachment of the virus. The acidic effector domain has been linked to a zanamivir anchoring domain, to facilitate attachment to virions via the neuraminidase (NA). This anchor not only provides proximity for the effector domain, but also suppresses the enzymatic activity of the NA and prevents spread of progeny virions, like a traditional NA inhibitor.
Methods
Eight-week-old BALB/c mice were administered a single intranasal dose of MD compound. Mice were given either 5ug 40 days before, or 40ug at 48 or 72 hours after, lethal challenge with 500PFU of A/PR8/34. We are also passaging viruses in vitro in the MD inhibitor to determine if we can select for resistance to this compound.
Results
Mice were completely protected from mortality, weight loss, and clinical signs when the MD compound was administered prophylactically, while 100% and 60% survival rates were observed when the compound was given at 48 hours or 72 hours post infection respectively.
Conclusions
We have developed a safe and effective influenza antiviral capable of extensive prophylaxis after a single low dose intranasal administration. This compound will fill a critical gap in our influenza pandemic response, as currently licenced antivirals (Zanamivir, Oseltamivir, and Baloxavir) all possess short half-lives, limited efficacy, or are prone to the development of resistance. We do not expect resistance to be a significant factor in the clinical application of the MD compound, since any novel mutants must overcome a dual mode of action.