excellent article posted on ss - resistance

Thanks to Jumper from SS

"One strength of the neuraminidase inhibitors oseltamivir and zanamivir (Relenza) over the older adamantanes is that they are less prone to selecting for resistant influenza viruses. Indeed, no virus resistant to zanamivir, which is currently available only in an inhaled form, has yet been isolated from immunocompetent patients after treatment. The recent emergence of oseltamivir-resistant variants is therefore a matter of immediate concern.

Why is resistance developing to oseltamivir? Several years ago,structural analysis predicted that aspects of the chemical structure of oseltamivir (not present in zanamivir) could facilitate the development of resistance mutations that would permit neuraminidase to function, allowing drug-resistant virus to survive and propagate. This prediction is now being validated by clinical data.

The mechanism of the development of resistance is illustrated in the diagram. The influenza neuraminidase releases newly formed viruses from infected cells, allowing them to spread from cell to cell. The inhibitor molecules mimic the natural substrate of the influenza neuraminidase (the sialic acid receptors) and bind to the active site, preventing neuraminidase from cleaving host-cell receptors and releasing new virus. All the resistant variants thus far have contained specific mutations in the neuraminidase molecule; but since neuraminidase serves an essential purpose, mutations that allow the virus to survive must not inactivate the enzyme.

To accommodate the bulky side chain of oseltamivir in the active site, the neuraminidase molecule must undergo rearrangement to create a pocket (Panel A). Zanamivir, by contrast, binds to the active site without any rearrangement of the molecule. Several mutations that limit the necessary molecular rearrangement may diminish the binding of oseltamivir (Panel B). Molecular-level analysis (Panel C) shows that the amino acid termed E276 must rotate and bond with R224 to form a pocket for the side chain of oseltamivir. The mutations R292K, N294S, and H274Y inhibit this rotation and prevent the pocket from forming, resulting in resistance to oseltamivir. The mutations nonetheless allow the binding of natural sialic acid substrate, so mutated virus can survive and propagate. In contrast, the binding of zanamivir does not require any reorientation of amino acids, so these mutated viruses remain sensitive to that drug. An E119V mutation also interferes only with oseltamivir binding, possibly because a water molecule can fit between oseltamivir and valine at the active site but cannot insinuate itself between zanamivir and valine at residue 119.

These mechanisms have clinical implications. The mutations identified in the resistant viruses have thus far all been in the amino acids mentioned above.


http://content.nejm.org/cgi/content/full/353/25/2633