New Class of Anti-Influenza Drugs Less Likely to Trigger Resistance

A team of molecular virologists has designed a small molecule drug that blocks the spread of the influenza virus more effectively and with less likelihood of triggering development of resistance than the currently available antiviral agents.

Drugs for treatment of influenza are neuraminidase inhibitors that target the virus' surface neuraminidase enzyme. They work by blocking the function of the viral neuraminidase protein, thus preventing the virus from reproducing by budding from the host cell. Oseltamivir (Tamiflu) a prodrug, Zanamivir (Relenza), Laninamivir (Inavir), and Peramivir belong to this class. Unlike the M2 inhibitors, which work only against influenza A, neuraminidase inhibitors act against both influenza A and influenza B.

The main failing of the currently used neuraminidase inhibitors is the rapid development of strains of the virus that are resistant to the drugs. To counter this problem investigators at Simon Fraser University (Burnaby, BC, Canada) searched for potential drugs that would be as efficient as the currently used drugs but less likely to trigger development of resistant strains of the virus.

They reported in the February 21, 2013, online edition of the journal Science Express that they had discovered—and confirmed the mode of action via structural and mechanistic studies—a new class of specific, mechanism-based anti-influenza drugs that functioned via the formation of a stabilized covalent intermediate in the influenza neuraminidase enzyme.

These compounds functioned in cell-based assays and in animal models, with efficacies comparable to that of the neuraminidase inhibitor zanamivir and with broad-spectrum activity against drug-resistant strains in vitro.

The investigators maintain that the similarity of the drugs' structure to that of sialic acid, the natural substrate of neuraminidase, and their mechanism-based design make them attractive antiviral candidates.

The new class of drugs is particularly effective due to its water solubility. “They reach the patient’s throat where the flu virus is replicating after being taken orally,” said contributing author Dr. Masahiro Niikura, associate professor of virology at Simon Fraser University. “Influenza develops resistance to Repenza less frequently, but it is not the drug of choice like Tamiflu because it is not water-soluble and has to be taken as a nasal spray. Our new compounds are structurally more similar to sialic acid than Tamiflu. We expect this closer match will make it much more difficult for influenza to adapt to new drugs.”

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