Scientists have found a potential cure for Ebola (Science Alert)

Ebola and related viruses cause hemorrhagic fever and death through organ failure, and can have a mortality rate of up to 90%, among the highest of any known human disease.  But researchers working in a high-contaminant biological laboratory maintained by USAMRIID at Fort Detrick in Maryland, US, may have found a potential cure.

The scientists have discovered a molecule, named BCX4430, (see structure) which looks a lot like the "A" that makes up DNA: adenosine. Adenosine is one of four base pairs in DNA, and is also used in the genomes of RNA-based viruses,  such as Ebola. But because BCX4430 looks so much like Adenosine, the scientists found that members of the Filoviridae virus family, such as Ebola, can accidentally use it as a building block when trying to grow inside our cells

  
In the study, the team gave Macaque monkeys effected with the deadly Marburg virus (a close relative to Ebola) two doses for BCX4430 a day  for 14 days.

The monkeys who weren't given any of the treatment were dead by day 12, whereas all but one monkey who was given BCX4430 survived, even if they only received treatment 48 hours after they were infected.

Luckily, only virus cells appear to be tricked into using BCX4430, and human and monkey cells do just fine with the molecule around. In vitro experiments
also suggest that BCX4430 could potentially be used against a wide range of
viruses, including SARS, influenza, measles and dengue.
It's too early to get excited just yet, with no human trials yet conducted. But the newly discovered molecule holds the greatest potential we've ever seen for curing these terrifying diseases.

http://www.nature.com/nature/journal/vaop/ncurrent/fig_tab/nature13027_F1.html

Scientists
have found a potential cure for Ebola (Science Alert)

Scientists identify promising antiviral compounds

Based on studies of the atomic-level structure of an enzyme that's essential for the maturation of adenovirus and how that enzyme becomes active  conducted at Brookhaven's National Synchrotron Light Source (NSLS) -- we used computational modeling to search for compounds that might interfere with this enzyme and tested the best candidates in the lab."

Out of 140,000 compounds in a national database, the scientists identified two they expect to be able to turn into antiviral agents to combat adenovirus.

This research is a great example of the potential for rational drug design…based on studies of the atomic-level structure of an enzyme…conducted at Brookhaven's National Synchrotron Light Source.

The need for such antiviral compounds stems from the diversity of human adenoviruses and their ubiquitous effects, Mangel said. Adenoviruses cause many types of respiratory diseases (including outbreaks among military recruits), childhood pneumonias, and eye infections -- and may even play a role in obesity. They are particularly dangerous for individuals with impaired immunity, such as transplant recipients and patients with AIDS.

With more than 50 varieties causing this range of diseases, it's unlikely scientists will develop a universally effective vaccine to prevent all strains of adenovirus before infection, Mangel said. But one thing all adenovirus strains share is a common mechanism of making new virus particles once an infection takes root. Targeting that mechanism with antiviral drugs -- the approach taken by the Brookhaven team -- may be a viable way to battle all adenovirus strains.

Mangel worked with fellow Brookhaven scientists William McGrath and Vito Graziano, along with Kathy Zabrocka, a student from Stanford University who was conducting an undergraduate internship in his lab. The research built on work Mangel's lab initiated years earlier to decipher the atomic-level structure of the adenovirus proteinase, an enzyme conserved throughout all strains of the virus that cleaves proteins during the assembly of new virus particles.

"Once those proteins are cleaved, the newly synthesized virus particle is infectious," Mangel explained. "If those proteins are not cleaved, then the infection is aborted. Thus, inhibitors of the adenovirus proteinase should be effective antiviral agents against all strains of adenovirus," he said.

Over several years, Mangel's group found that the activity of the enzyme was highly regulated by two cofactors, a small piece of another adenovirus protein and the viral DNA. Structures of the enzyme alone and in the presence of its cofactors, determined by x-ray crystallography at the NSLS, revealed key regions that could serve as potential targets for blocking the enzyme's activation or protein-cleaving ability.

"All that remained was to find compounds that bind to these targets to prevent the enzyme from functioning," Mangel said.

To find these compounds, the scientists used a technique called DOCKing, which entails computationally probing a region of the protein structure against databases of small molecules to determine which might bind most strongly. Out of a database of 140,000 potential compounds, the scientists identified 30 molecules predicted to fit best and ordered samples to test for inhibitor activity.

Two of the molecules (NSC-36806-left struct;  and NSC37249 right struct) that DOCKing identified turned out to be excellent inhibitors of the adenovirus proteinase. At the concentrations that inhibited the adenovirus proteinase, these same compounds did not inhibit other, similar enzymes. Thus, the compounds appear to be specific inhibitors of the adenovirus enzyme.

Ref : http://www.sciencedirect.com/science/article/pii/S0014579313003876  

The molecules identified are still too large to be delivered as drugs. So the scientists are working to pare down the size in the design of a second-generation compound based upon the binding portions of the two inhibitors. This new molecule is expected to readily enter adenovirus-infected cells and bind even more tightly to the adenovirus proteinase.

"This work should pave the way for the development of effective drugs against all types of adenovirus infections," Mangel said...

Scientists identify promising antiviral compounds