Enzyme discovery holds promise for SARS, MERS vaccine
A new study led by researchers from Purdue University in West Lafayette, IN, details a way of disabling a part of the virus involved in severe acute respiratory syndrome that allows it to hide from the immune system - a finding that may lead to the development of a vaccine against the disease.
The research team, led by Andrew Mesecar, professor of cancer structural biology at Purdue, says their findings may also lead to the creation of a vaccine against Middle East respiratory syndrome (MERS) - a virus related to severe acute respiratory syndrome (SARS).
During the 2003 SARS outbreak, a total of 8,098 people worldwide became sick with the disease. Last month, the Centers for Disease Control and Prevention (CDC) confirmed the first MERS infection in the US, prompting nationwide concern.
As yet, there are no drugs that work against MERS and SARS, but it is certainly not through lack of trying. Medical News Today recently reported on a study led by researchers from the University of Gothenburg in Sweden and the University of Berne in Switzerland, which detailed the discovery of a compound that inhibits the coronaviruses involved in MERS and SARS.
In this latest study, recently published in the journal PLOS Pathogens, Mesecar and his colleagues identified the molecular structure of papain-like protease (PLpro) - an enzyme that plays an important role in the development of SARS.
The researchers discovered that the enzyme removes a host cell in ubiquitin and ISG15 - proteins that play a role in activating an immune response - effectively hiding it from the immune system.
"With most viruses, when a cell is infected it sends out an alarm triggering an immune response that fights the infection, but successful viruses are able to trick the immune system," explains Mesecar.
"By clipping off these two proteins, SARS short circuits the host cell's signaling pathways and prevents it from alerting the immune system to its presence. By removing these proteins, the enzyme serves as a biological cloaking system for the SARS virus that allows it to live and replicate undetected."
In addition, Mesecar says that disrupting signaling pathways may also cause infected cells to miscommunicate with each other - but this is not a good thing.
"Some treatments prevent a virus from replicating and stop further infection, but that doesn't necessarily prevent a harmful reaction to the virus. Sometimes it is the confusion in cellular communication that makes a virus lethal," Mesecar explains.
Vaccine 'needs to retain cell replication while encouraging immune response'
The team also discovered that the PLpro enzyme divides the viral polyprotein in SARS into individual proteins - a process that is crucial for viral replication. This process, Mesecar says, is the one that a vaccine needs to maintain.
This latest discovery may lead to the development of a vaccine against SARS and MERS, the researchers say.
He explains that a vaccine for the SARS virus needs to retain the viral replication process while still encouraging an immune response. "We want enough viral particles to be generated to properly prime the immune system to fight off a true infection, but without the virus being able to cause illness in the vaccinated individual," he says.
As such, the researchers analyzed the SARS PLpro enzyme in order to determine the areas responsible for inhibiting an immune response that could be modified without disturbing viral replication.
Using X-ray crystallography, the researchers were able to look at a 3D structure of how the PLpro enzyme interacted with the ubiquitin protein and determine what amino acids combine the two. In addition, the team used computer models and simulations to see what amino acids bind PLpro and ISG15 together.
Once the amino acids were identified, the researchers mutated them so the PLpro enzyme was unable to communicate with ubiquitin and ISG15 - therefore the SARS virus was exposed to the immune system. The team then tested the PLpro enzyme to ensure it was still able to trigger the viral replication process.
Commenting on these findings, Mesecar says:
"This is a first step toward creating a weakened and safe virus for use in an attenuated live vaccine. This also could serve as a molecular roadmap for performing similar studies on other coronaviruses, like MERS, because this enzyme appears to be common to all viruses within this family."
The team says they are already in the process of testing these findings on the MERS virus.
Written by Honor Whiteman
Copyright: Medical News Today
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