May 25, 2005 WEST LAFAYETTE, Ind. – An antiviral compound that wiggles its way into the common cold virus may provide one piece of the solution to halting the infection, say Purdue University scientists.
Using computer simulations, a team of scientists led by Carol B. Post has found the likely reason why a WIN compound – a prototype drug for curing colds – is showing so much promise. The flexible molecule's structure may allow it to shimmy inside the proteins that form the virus' outer shell and alter them to the point where they cannot complete the infection process. An animated video of the computer simulation illustrates some of the results the team describes in its research paper, which appears in Tuesday's (May 24) issue of the scientific journal Proceedings of the National Academy of Sciences.
"Flexibility appears to be an important characteristic for a drug to possess if it is to be successful at neutralizing rhinoviruses, which often cause the common cold," said Post, who is a professor both of medicinal chemistry in Purdue's College of Pharmacy, Nursing and Health Sciences and of biological sciences in the College of Science. "WIN compounds are not going to cure the cold anytime soon, but our analysis of their behavior may have shown us why they are so good at foiling these viruses. Their flexibility allows them to reach a weak spot in the viral shell."
Post carried out the study with Purdue colleague Zhigang Zhou, a postdoctoral researcher in the Department of Medicinal Chemistry and Molecular Pharmacology, and Yumin Li, who performed the work as a Purdue postdoctoral researcher but has since accepted a professorship at East Carolina University in North Carolina. Post and Li prepared the animation.
Rhinoviruses, perhaps best known as one cause of the common cold, have complex surfaces made up of a mosaic of protein molecules. Groups of these proteins organize themselves into pentagonal and hexagonal forms that give each virus a protective shell, or capsid, resembling a soccer ball. But the outer surface of this soccer ball can change its appearance subtly so the body's defenses cannot recognize it.
"Ordinarily our systems make antibodies to clean out invaders like viruses," Post said. "But the rhinovirus has many faces. Each time a new one infects us, its outer surface may have mutated from a previous cold virus so that our antibodies can't recognize the new one. The common cold virus can hide in a crowd because it always looks like someone else – it's the bug of a hundred faces."
The viral shell also changes shape during the life cycle of a single rhinovirus particle. One part of the shell that seems to guide these shape changes is a small, cigar-shaped cavity within the folds of a protein called VP-1 that forms around the capsid's pentagonal groups.
"We've known that filling the cavity is key to curing the common cold," Post said. "Now we're learning why. The secret may be that filling the cavity stops the virus from changing shape at a critical moment."
When attacking a cell, the rhinovirus particle undergoes perhaps its most important change in shape after the virus has gained entry into a cell. Once inside its victim, the pentagons open up like the trap door in the fabled Trojan horse, allowing the RNA within the virus to spew out and instruct the cell to begin producing more rhinovirus particles. This change is possible because the capsid proteins, including VP-1, are themselves flexible enough to allow the trap door to open and let the genetic material out.
"What we'd like to do is find something that will stabilize these VP-1 proteins so the trap door can't open, and WIN compounds are potential candidates for the job," Post said. "In essence, the compounds can get tangled up in the protein so it can't move enough to let the RNA out. Once reason WIN compounds are promising is that they are very good at getting to the spot where they can tangle up the protein effectively, which turns out to be a tricky business."
That spot is located in the cigar-shaped cavity within the protein, a cavity accessible only by a tiny hole that on first inspection looks too narrow even for the stringy WIN molecule to squeeze through. And it would be too narrow, Post said, if the two molecules were not always vibrating with thermal energy.
"Because both the protein and the WIN compound are always in motion, the compound is able to shimmy its way through the hole by twisting itself around," Post said. "If it gets stuck for a moment, it can twist its way through by means of atom-sized hinges and swivels along its length. It turns out that even in the molecular world, it helps to be flexible."
The team discovered the effect through a computer simulation of the molecules' behavior, which they animated as a brief movie. The analysis actually concerned how the WIN compound exits the cavity, but Post said their work is relevant to movement in either direction.
"The compound can both enter and leave the pocket, and goes through the same twists in either direction," she said. "The animation shows WIN entering the pocket, which is simply our simulation run in reverse."
Computer analysis also showed that the WIN compound, once entrenched within the cavity, affects the rigidity of the protein even at considerable distances away from where the compound is lodged – a most beneficial effect for deactivating the virus, but one the team cannot yet explain.
"We thought the WIN compound was affecting the protein's rigidity in a small but significant region around the cavity, but our analysis suggests that the stiffness may extend farther than that to the region of the trap door itself, which could be one reason why WIN compounds are good at stopping these viruses from opening up," Post said. "We don't have a scientific explanation for such a long-distance effect yet. But just as people don't feel like exercising after eating too much, having a WIN compound in its cavity may be the VP-1 protein's equivalent of having an overly full stomach."
Post said that while WIN's behavior reveals a significant characteristic that antiviral compounds will need, the findings would not produce a cure for the common cold on their own.
"Among the hurdles that still stand in our way is any toxicity to our systems that these WIN compounds may have," she said. "But seeing these molecules in motion may help improve our approach to drug development and has revealed some fundamental details about the workings of viruses as well."
This research was sponsored in part by the National Institutes of Health.
Post's group is associated with the Markey Center for Structural Biology and the Purdue Cancer Center. The Markey Center consists of laboratories that use a combination of cryo-electron microscopy, crystallography, and molecular biology to elucidate the processes of viral entry, replication and pathogenesis. One of just eight National Cancer Institute-designated basic-research facilities in the United States, the Cancer Center attempts to help cancer patients by identifying new molecular targets and designing future agents and drugs for effectively detecting and treating cancer.
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