🤧 Discovery could lead to drugs against the common cold

• Researchers have for the first time determined the structure of the protein 2C as it binds to RNA.
• The protein is found in rhinovirus, the most common cause of the common cold, and is a target for drugs.
• The new structure gives researchers more to work from when they design drugs that can inhibit the virus.

A target for drugs against several viruses

Researchers at Stanford University and The Pirbright Institute, among others, have produced the first structure of the protein 2C bound to RNA. The protein is found in picornaviruses. Rhinovirus, the most common cause of the common cold, belongs to this group.

2C is needed for the virus to copy its genome. The protein is already a target for drugs that can work against several picornaviruses at once. Because the common cold virus is a picornavirus, and has the same protein with the same key parts, it is one of the viruses such a drug could target.

The researchers included human rhinovirus A in their analysis. The three amino acids that matter most for 2C to bind to RNA sit in the same structural position in the common cold virus as in the virus the researchers built their structure from.

A basis for drug development

Earlier proposals for drugs against 2C have been based on the structure of a single copy of the protein. That structure lacks the details that appear when six copies come together with RNA. The new structure gives researchers more to work from when they design small molecules or peptides that can inhibit the virus.

First image of the protein bound to RNA

The structure shows that six identical copies of the protein come together to form a ring. The ring is about 10 nanometers in diameter. A single strand of RNA runs through a central pore in the middle of the ring.

The researchers used cryo-electron microscopy. They analyzed 260,225 particles and reached a resolution of 3.05 Ångström, which makes it possible to see the individual parts of the protein. The study has been published as a preprint and has not yet been reviewed by other researchers.

Three amino acids determine the binding

The researchers identified three amino acids that matter most for the protein to bind to RNA: A188, L190 and K193. A fourth, H147, is needed for the protein's function.

The amino acid A188 lets the protein tell RNA apart from DNA. This is due to an oxygen atom that binds to a part found only in RNA. When the researchers swapped out the key amino acids, binding to RNA dropped. In experiments with foot-and-mouth disease virus and coxsackievirus B3, the virus then stopped replicating.

Viruses behind billions of infections

Picornaviruses cause at least 8 billion infections a year in humans. Symptoms range from upper respiratory infection to paralysis. Enterovirus D68 has been linked to acute flaccid myelitis in children, and EV-A71 has led to paralysis and death in children in several places around the world.

Among animals, foot-and-mouth disease virus causes large losses. The disease in livestock costs about 21 billion dollars globally. Respiratory infections from picornaviruses in the United States are estimated to cost about 40 billion dollars. There are few approved drugs against picornaviruses besides polio.

The same building parts in many virus families

The key amino acids are not found only in picornaviruses. The researchers searched for similar proteins across the entire order Picornavirales and found 497 hits in several virus families, including the family the norovirus belongs to. The norovirus has the protein NS3, which has many of the same parts that 2C uses to bind RNA.

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