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.

This article was originally published with the title Charging against the Flu.

6 Comments

1. 1. boxes 08:17 PM 2/11/11

   Oh my goodness. I'm a solid-state NMR spectroscopist, and this article is making its circulation through my research group. I laughed so hard I cried, there are so many things wrong with the description of the NMR technique...

   Reply | Report Abuse | Link to this

2. 2. 4karats 12:49 AM 2/12/11

   I hope boxes can tell us what things are wrong with the description of the NMR technique described by Scientific American. Spread the laughs not the flu. Cheers.

   Reply | Report Abuse | Link to this

3. 3. boxes 06:48 PM 2/14/11

   Certainly. Well, I'm not going to write that much (if you're interested in the NMR technique, Google can probably do a decent job of finding something more in depth.)
   
   My biggest problem with this article is the way in which the author uses the word 'spin.' NMR does take advantage of something called spin, but it's a quantum mechanical property, NOT an action. It is absolutely wrong to say that nuclei (as an action) spin up or spin down. Rather, protons (and other spin-1/2 nuclei) can occupy states designated as "spin up" and "spin down." The nuclei are never actually spinning... the name was chosen because they behave, somewhat, as though they are (i.e. they possess angular momentum). What the strong static magnetic field does is affect the energy levels of these spin states (without an external magnetic field they have the same energy, in other words, are degenerate). Within the magnetic field, the spin states have different energies, and applying radiofrequency radiation stimulates transitions between these states (this is what NMR is all about).
   
   The author states, "different tissues 'spin down' at different speeds." I am going to assume that this is a misinterpretation of something called spin-lattice relaxation, which describes how the system returns to its equilibrium state after being perturbed (i.e. excited by the RF radiation). Basically, the excess energy is lost to the "lattice," or surroundings, and this happens at different rates depending on the tissue. This is, I repeat, NOT called "spinning down," in fact, more nuclei exist in the "spin up" state at equilibrium!
   
   The author states that there is a difference with the magnetic fields of NMR and MRI. There isn't. On average, the field strengths in MRI are lower, but both the magnetic fields used in NMR and MRI split the energy states (break the degeneracy) of ALL NUCLEI that are NMR-active. That you cannot observe some nuclei in MRI is not a fault of the magnet, it's usually due to low concentrations in the human body, and hardware limitations that arise when designing a magnetic field that is homogeneous over a sample the size of a human body.
   
   Another thing. As previously stated, NMR deals with transitions between spin states. It has nothing to do with charge. Nuclei are not given any sort of nonequilibrium charge in the experiment, and therefore do not "return to their normal charge," as the article states. For this reason, even the title of the article (which I'm assuming is supposed to be a clever play on words) is completely off the mark.

   Reply | Report Abuse | Link to this

4. 4. boxes 06:54 PM 2/14/11

   Some nitpickier things: NMR spectroscopy does not generate images, it generates spectra.
   
   The author continuously uses the word "hydrogen," but to be technically correct, they should say "protons." Hydrogen exists in three different, stable isotopes, protons, deuterons, and tritons. All three of these isotopes have DIFFERENT NMR properties.
   
   Anyway, this has become something of a rant, so I apologize for that. I'm just highly disappointed in whoever did the research for this article.

   Reply | Report Abuse | Link to this

5. 5. bucketofsquid in reply to boxes 11:53 AM 2/28/11

   SciAm has to balance the accuracy of any given article against the struggle to be accessable enough to maintain a profitable level of readership. Articles like this are the result. It is simple enough that the people not working in this field can get a grasp of the general impact without getting bogged down in jargon we don't understand. It would be nice if the SciAm articles had a multi-layered approach for those more in the know or less in the know to be able to choose the level of detail they want.
   
   I greatly appreciate your explanations because I'm trying to get a handle on quantum mechanics to keep up with my son. He wants to get into neuro-biology and learn how the cells of the brain work at an atomic and molecular level. He is already at the limit of what I know and while I can't teach him anything I would like to be able to ask about what he is learning when he gets to college in a couple of years.

   Reply | Report Abuse | Link to this

6. 6. boxes 01:29 PM 3/1/11

   My issue is not with generality. I've looked over many other SciAm articles regarding NMR, and most of them do a really good job of keeping things simple yet accurate. My problem with this article is that it is not at all accurate (I'm not talkin' a few errors here and there. I mean way way off.) I'm glad my comments helped and it's nice to see that you've taken an interest in your son's work (my parents just smile and nod when I talk to them about what I do.)
   
   My suggestions is to ask your son if there are any magazines more directly related to his field that are aimed at a general audience -- they usually come with the layered approach you mentioned.. at least the ones in my field do. It's a good way to stay up to date on current research in a specific field, as well as learn the basics.

   Reply | Report Abuse | Link to this