A new class of compounds that can fight influenza by preventing the virus from spreading has been developed by an international team led by chemists from the University of British Columbia. The molecules have been shown to be effective even against strains that are resistant to current treatments.
Hemagglutinin and neuraminidase are two key proteins displayed on the surface of the virus particle; they are the H and N used in virus strain names like H1N1. Hemagglutinin binds to sialic acid, a sugar moiety on the surface of many cells. Once bound, the virus is brought inside the cell and replicates. New virus particles then migrate back to the cell surface, but are still held by the hemagglutinin-sialic acid bond. Neuraminidase cleaves off the sialic acid, releasing the virus to infect other cells. Flu drugs like Tamiflu and Relenza are sialic acid mimics, and work by binding to the neuraminidase and blocking its action. Unfortunately, some virus strains are evolving resistance to these drugs.
Stephen Withers and his team have spent decades studying the mechanisms by which enzymes like neuraminidase interact with sugars like sialic acid. “The normal mechanism involves an intermediate form of the sugar that makes a covalent bond with the enzyme,” says Withers. By designing a sialic acid derivative — 2,3-difluorosialic acid (DFSA) — which forms a more stable version of that covalent bond, Withers and his team hoped to block neuraminidase and stop the spread of the virus.
In a paper published in Science, the team showed that although DFSA worked, it inhibited human enzymes as well as the viral ones, so new compounds were modified with either an amine or a guanidine group to make them more selective. The best of these inhibited neuraminidase derived from resistant flu strains at concentrations of only a few nanomoles per litre; current flu drugs required concentrations 10 to 100 times higher to do the same. Withers says it will take several years to turn these molecules into drugs, but he’s confident they can remain effective on their own or in combination with current treatments. “This ‘cocktail’ approach has been used with HIV drugs: the probability that one virus can mutate against three drugs at the same time is pretty low,” he says. “My guess is that will be the standard of care in the future.”