Study Indicates Target for Future Drugs for Measles, Ebola, RSV
University of Utah physics doctoral student Xiaolin Tang and virologist Saveez Saffarian in the lab where they identified an exotic mechanism that may explain how a group of viruses that includes Ebola replicate or make copies of themselves to make people sick. Photo Credit: Lee J. Siegel, University of Utah
Dec. 11, 2014 – University of Utah researchers ran biochemical analysis and computer simulations of a livestock virus to discover a likely and exotic mechanism to explain the replication of related viruses such as Ebola, measles and rabies. The mechanism may be a possible target for new treatments within a decade.
“This is fundamental science. It creates new targets for potential antiviral drugs in the next five to 10 years, but unfortunately would not have an impact on the current Ebola epidemic” in West Africa, says Saveez Saffarian, senior author of a new study published today by the Public Library of Science journal PLOS Computational Biology.
Saffarian, a virologist and assistant professor of physics and astronomy, and his colleagues studied a horse, cattle and pig virus named VSV – vesicular stomatitis virus – which is a member of family called NNS RNA viruses. That family also includes closely related viruses responsible for Ebola, measles, rabies and the common, childhood respiratory syncytial virus, or RSV. The genetic blueprint in these viruses is an RNA strand that is covered by protein like beads on a necklace.
By conducting 20,000 computer simulations of the VSV starting to replicate in different possible ways, the study found a “fundamental mechanism” used by VSV and related viruses like Ebola to make copies of themselves or replicate, Saffarian says.
The mechanism: Once the virus infects a cell, enzymes called polymerases literally slide along the protein “bead”-covered viral RNA strand until they reach the correct end of the strand. Then the polymerases can read and “transcribe” the RNA code to synthesize messenger RNA, or mRNA. Once one polymerase starts doing that, it collides with other sliding polymerases, kicking them loose within the cell until they, too, attach to the correct end of the RNA and start making copies. That lets the virus replicate and take over the infected host cell.
“The proposed sliding mechanism is a fundamental new mechanism specific to the NNS RNA viruses that can be a target for antiviral drugs in the future,” Saffarian says – something he hopes pharmaceutical scientists will pursue.
The sliding contrasts with replication in many other viruses, in which the polymerases easily detach from the virus inside an infected cell and then find the right end of the RNA so replication begins.
The mechanism was discovered by computer simulations, so “we are working now on demonstrating evidence of the sliding mechanism in VSV,” Saffarian says.
He believes the discovery is “as fundamental as understanding the workings of HIV protease” – an enzyme essential for replication of the AIDS virus and that became a target of protease inhibitors, which first made it possible for AIDS patients to live with AIDS as a chronic rather than deadly disease.
Saffarian conducted the study with first author and physics doctoral student Xiaolin Tang, and with research scientist Mourad Bendjennat. The National Science Foundation funded the study.