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					Studying the Flu Virus on the
Atomic Level
By Jessica Wapner February 10, 2011


A giant magnet is illuminating how the influenza A virus mutates to
resist drugs




                        Image: Cordelia Molloy Photo Researchers, Inc.


With the flu now resistant to its two most common medications, doctors and drug
developers have grown increasingly puzzled about how to treat the virus. A 900-
megahertz magnet is offering some new clues. Biochemists at Florida State University
and Brigham Young University have used a 40-ton magnet to obtain atomic-level images
of the virus, not only confirming how the bug escapes annihilation but also revealing
potential pathways for new drugs.


The study focused on influenza A, the virus responsible for pandemic strains—more
specifically, on one of the virus’s surface proteins known as M2, which plays an
important role in reproduction. Antiviral drugs amantadine and rimantadine, which for
years were the most widely used against influenza A viruses, plugged the M2 pathway
like bathtub stoppers, preventing reproduction. Over the years, however, changes in
M2’s shape enabled it to slip by those stoppers and avoid eradication; in 2006 the
Centers for Disease Control and Prevention recommended against the use of these two
drugs. Although the general mechanism of resistance has been known for some time,
exactly how M2 functions was less clear.


The big magnet gives an inside view of the virus, much like magnetic resonance imaging
can be used to peer inside our limbs and organs. The approach, called solid-state nuclear
magnetic resonance spectroscopy, delivers images similar to MRI, but with key
differences. The magnetic field generated during an MRI scan spins the hydrogen in
water molecules into alignment. The resulting image—of a knee, a brain, a tumor—is a
snapshot of the molecules as they return to their normal charge; different tissues “spin
down” at different speeds. But the M2 protein exists at the water-repellent cell
membrane, making MRI scans impossible. The charged field generated by NMR
spectroscopy can spin elements other than hydrogen, making it possible to image
proteins that do not live in a watery medium. In addition, samples can be frozen, making
observations of slippery proteins like M2 easier.


By focusing on nitrogen atoms, Timothy A. Cross of Florida State University and his co-
workers were able to determine exactly how M2 functions. They found that the protein,
shaped like a channel with pores at both ends, has to be activated by an acidic
environment to function. Two amino acids—histidine and tryptophan—set the process in
motion: histidine carries protons from the host cell into the viral interior, and
tryptophan acts as a gate, swinging open when the protons arrive. This passage of
protons through the M2 pores is what allows the virus to reproduce.


According to the findings, reported recently in Science, M2’s mechanism is completely
unique, which could be good news for drug developers. “Maybe we can design a drug that
would specifically target this [novel] chemistry,” says Cross, who notes that the virus’s
reliance on M2 might make mutating against such a specialized drug difficult.


Cross and his team are screening drug compounds against the virus but have yet to
identify serious candidates.

				
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