Tiny Viruses, Big Controversy

Research Blogging / by Dave Munger /

A recent dispute over the active mechanism for adamantanes, antiviral drugs that combat influenza, sheds light on the difficulties of designing effective antiviral therapies.

Credit: Flickr user kat m research

Modern antibiotics have a history more than a century long, marked by dramatic successes such as Alexander Fleming’s 1942 discovery of penicillin. They have done a remarkable job combating diseases and infections caused by bacteria, like pneumonia and strep throat. By contrast, antiviral drugs for viral diseases like influenza and AIDS have had much more limited success.

One of the first drugs to show any ability to combat a viral infection, adamantane, was found to be an effective treatment for some forms of influenza in the 1960s, largely by trial and error. It is only recently that researchers have begun to get some idea of how it works. Unfortunately, as Brazilian biologist Atila Iamarino points out, nearly all strains of the flu, including the recent deadly H1N1 outbreak, are now resistant to adamantanes.

This new resistance is caused by a mutation to a critical part of the virus’s replication apparatus. Like all viruses, influenza can’t reproduce on its own; it needs to hijack another organism’s cells to duplicate itself. Once the virus is inside a host cell, it must have a way determine that it is near the cell nucleus. In the case of influenza, the virus takes advantage of the fact that pH tends to be lower (more acidic) near the nucleus—DNA and RNA are called “nucleic acids” for a reason. A protein called M2 on the virus’s surface admits hydrogen ions found in acidic environments, which in turn starts the viral replication process. In some unmutated flu strains, adamantane stops this process. But how? And how did the mutation prevent adamantane from working? These are critical questions, because if we can learn how the mutation works, we may be able to design new drugs to circumvent it.

The problem has proven extremely difficult for biologists to unravel. While you may have seen beautiful schematic images of complex biological molecules like DNA, RNA, and proteins in textbooks, in practice, researchers can only infer the structure of these tiny particles using techniques like x-ray crystallography and NMR spectroscopy. In the hazy world of biochemical analysis, two powerhouse labs have battled for nearly a decade to puzzle out how adamantanes work, and the story has engendered a genuine scientific controversy.

In 2008, each lab published its own explanation of how adamantane bonded to the influenza virus, and biochemists Nick Anthis and Michael Clarkson explained the research on their blogs.

The DeGrado lab argued that the adamantane effectively blocked the center of the pore created by M2 on the virus surface, thus preventing hydrogen ions from entering the virus and initiating replication. The Chou lab countered with a somewhat more complicated model, requiring several adamantane molecules to bind with M2 at a different location, but with the same result: The pore was constricted, and replication was halted.

Remember, the researchers couldn’t just look in their microscopes and observe the tiny molecular structures; they had to infer them through other indirect techniques. The Chou lab, in research led by Jason Schnell, used NMR spectroscopy, which analyzes the radiation emitted and absorbed by atoms within the molecules to determine how those molecules bond and form larger structures. The advantage of this technique is that the molecules can be in a liquid solution, much like they would be in a human body. The DeGrado lab, in work led by Amanda Stouffer, used x-ray crystallography, which can produce more accurate results, but requires that the molecules under analysis be in a solid state. Clarkson points out that both methods involve only small portions of the structures they study—neither is a fully accurate rendering of the cellular environment the virus actually inhabits. So, in 2009, while Anthis favored the Chou model, Clarkson felt the contest was a near-draw. Everyone agreed that much more work was needed to solve the problem.

Now, says Clarkson, the picture has become dramatically clearer. A series of experiments found evidence for both explanations of M2 binding of adamantanes, but as the research progressed, the most realistic simulations supported the DeGrado lab’s pore-blocking model. The study linked above, led by Sarah Cady in a collaboration between the Mei Hong lab and Degrado’s lab, duplicated DeGrado’s results in a setting similar to the Chou group’s original study, suggesting that the DeGrado model is much more robust.

But that doesn’t mean that the Chou lab’s research is worthless, Clarkson says. Even though adamantine likely doesn’t work the way Schnell and Chou suggested, it’s possible that a new drug could utilize the mechanism they initially proposed for adamantine. After decades of person-hours of research, we not only have a fairly solid answer to the question of how adamantine works to stop the flu virus from replicating, we also have two solid leads on which to build a cure that’s immune to some of the flu bug’s persistent mutations

Dave Munger is editor of ResearchBlogging.org, where you can find thousands of blog posts on this and myriad other topics. Each week, he writes about recent posts on peer-reviewed research from across the blogosphere. See previous Research Blogging columns »

 

Originally published August 11, 2010

Tags biology data medicine

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