Molecular explanation for the evolution of Tamiflu resistance found

Caltech biologists have identified molecular changes that have assisted resistance in the antiviral drug Tamiflu, according to a statement released by Caltech officials.

Unlike vaccines, which stimulate the immune system to respond to the pathogens after an infection is established, Tamiflu and other antiviral drugs directly target viruses, according to study leader David Baltimore, Caltech’s Robert Andrews Millikan Professor of Biology and recipient of the 1975 Nobel Prize in Physiology or Medicine.

Baltimore, along with co-author Jesse D. Bloom, concluded that Tamiflu prevents a natural cycle in which neuraminidase - the N in H1NI - is cleaved from a sialic acid.

“It does this by binding in the 'active site' of the neuraminidase molecule, where neuraminidase normally cleaves sialic acid,” Bloom said.

For a virus to become resistant to Tamiflu, the neuraminidase protein has to be able to tell the difference between sialic acid and Tamiflu, the authors report.

“This study shows how combining an understanding of molecular mechanisms underlying evolution with the extensive sequencing data on historical isolates of influenza virus can bring about a deeper understanding of the challenge that this virus presents to the human population,” Baltimore said. “Only by marshaling a wide range of available information was it possible to understand why the virus could suddenly tolerate mutations that were previously deleterious. It shows that mutations are not necessarily 'good' or 'bad,' but that their effects may depend on the context in which they appear.”