Targeting the Achilles' heel
of MERS virus

Molecules shut down activity of an essential viral replication enzyme 

The behavior of MERS 3C-like protease when ligands are absent and present.

The MERS virus is in the international spotlight again as South Korea faces the largest outbreak outside the Middle East. As of July 30, the World Health Organization reported 36 deaths and 186 confirmed cases in South Korea and China.

In a paper published in the Journal of Biological Chemistry, researchers studying the viral enzyme nsp5, aka 3C-like protease, successfully blocked its function with inhibitor molecules. In the process, they also uncovered behavior that differentiates the enzyme from its counterpart in other coronaviruses.

“This enzyme is a prime target — an Achilles’ heel of MERS and other coronaviruses — and we were thrilled our inhibitor worked, but the results were puzzling,” says Andrew Mesecar, a professor of structural biology at Purdue University, who leads the research team. “The behavior was very different from what our work with SARS and other related coronaviruses predicted.”

Inhibitor helps MERS 3c-like protease form a dimeImages courtesy of Mesecar lab at Purdue University

3C-like protease is responsible for slicing a long strand of viral protein into smaller individual proteins that serve various roles in viral replication. Without it, the process shuts down, Mesecar says. Like other enzymes of its type, 3C-like protease must form a dimer to perform its function. The dimer is formed when two identical single 3C-like protease monomers join together.

Most coronavirus monomers have a strong attraction to their identical counterparts. However, Mesecar and his colleagues found that the MERS protease monomers do not have a strong attraction for one another and do not form its dimer readily. The researchers found that a MERS 3C-like protease monomer will remain single much longer and its dimer will break apart much more easily than those of other coronaviruses, he says.

However, when the team added small amounts of inhibitor molecules to interact with the protease, its activity increased.

“We were surprised to see that this inhibitor molecule that could potentially shut down the virus may also have the potential to increase its activity,” he says. “At low inhibitor concentrations we saw an increase in the protease’s activity, but at high concentrations it was shut down completely.”

It turns out that the MERS protease requires a ligand in order to form a strong dimer. The intended ligand is part of the strand of viral protein it is meant to cut, but the team found that the inhibitor molecule also did the trick.

“At low concentrations the inhibitor served as the ligand and triggered the protease to rapidly form a dimer,” he says. “If the second protease in the dimer had a vacant binding site, it was capable of binding to and cutting the strand of viral protein necessary for replication. However, at higher concentrations, we filled the target sites of all of the 3C-like proteases and its activity was successfully blocked.”

The team studied the interaction of the inhibitor molecule with 3C-like protease isolated from the MERS virus and next plans to study the interaction of the inhibitor with a complete virus inside a cell.

Elizabeth K. Gardner Elizabeth K. Gardner is a science writer and public information officer for Purdue University.