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."