Small molecules against Ebola: NMR reveals drug leads

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Ezine

  • Published: Feb 15, 2011
  • Author: David Bradley
  • Channels: NMR Knowledge Base
thumbnail image: Small molecules against Ebola: NMR reveals drug leads

Research fever

There is neither vaccine nor cure for the Ebola and Marburg viruses, which cause fatal haemorrhagic fever in humans. However, a new NMR spectroscopic study by US researchers scientists has led to the discovery of a family of small molecules that apparently bind to the outer protein coat of the virus and halt its entry into human cells, so offering the possibility of an antiviral medication against the disease.

The Ebola and Marburg viruses have a protein coat that envelops a non-segmented, single-stranded RNA. They emerge and spread quickly causing death in 9 out of 10 people infected and have reportedly killed more than 2300 people. More than 50% of those cases was during the 2000s. There is evidence that Ebola also affects gorillas in west-central Africa.

Now, in work largely funded by the US National Institutes of Health researchers at the University of Illinois at Chicago have found a new class of small molecule drug candidates that bind to the outer protein shell of the Ebola virus, which could prevent them from entering human cells. The team describes the work in detail in the Journal of Medicinal Chemistry.

UIC's Duncan Wardrop points out that other teams have identified drug candidates against Ebola but their mode of action tends to be one of changing the response of body cells to the virus once it has already entered the cell, at which point it is probably too late to prevent the onset of symptoms. The new molecules show that it might be possible to bind to the virus before it actually infects cells. Wardrop worked with UIC virologist Lijun Rong who developed a drug screening assay using a chimera of HIV and Ebola virus (specifically an Ebola Zaire GP-pseudotyped HIV particle with a luciferase reporter gene and 293T cells) that has the protein coat of Ebola; in other words, the chimera looks like Ebola but isn't life-threatening for scientists to work with under normal viral research conditions.

Testing times for Ebola drugs

The researchers tested some 230 candidate compounds against the new assay and found two likely molecules that inhibited entry of the virus. However, just one of these was specific to Ebola virus, the second compound could also have activity against Marburg virus, another deadly virus related to Ebola and has a promising effective dose. "That [finding] was a nice surprise," says Wardrop. "There's growing evidence that the two viruses have the same cell-entry mechanism, and our observations appear to point to this conclusion."

With the dual-function lead molecule, an isoxazole, in hand, Wardrop's graduate student Maria Yermolina synthesized a series of analogues of this compound in order to find a derivative that would have increased activity against Ebola infection. The synthesis of analogues is guided by the work of team member Michael Caffrey, a biochemist and molecular geneticist, who used nuclear magnetic resonance spectroscopy to investigate the binding. NMR was, of course, used as part of the synthetic program for generating the new compounds. "This knowledge may spur development of new anti-viral agents," Wardrop said.

The team admits that it is too early to predict whether the findings will lead to a new treatment for Ebola or Marburg infections. Wardrop is, however, positive that the results so far do raise some hope of developing an effective drug. The next step will be to test the lead compounds in an animal model. "From a wider perspective, we're searching for compounds to use as probes to study biological processes. Small molecules which bind to specific proteins and alter their function are invaluable to understanding what these proteins do in living cells," Wardrop says.



The views represented in this article are solely those of the author and do not necessarily represent those of John Wiley and Sons, Ltd.

 Structure credit: American Chemical Society. There is neither vaccine nor cure for the Ebola and Marburg viruses, which cause fatal haemorrhagic fever in humans. However, a new NMR spectroscopic study by US researchers scientists has led to the discovery of a family of small molecules that apparently bind to the outer protein coat of the virus and halt its entry into human cells, so offering the possibility of an antiviral medication against the disease.
Ebola drug candidate
Credit: J Med Chem/ACS

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