The Future of Fighting Viruses Is Blocking the Protein Fangs of Infection

Some large part of the difficulty in fighting the Ebola virus is that it's a moving target. This isn't to say moving in the geographic sense—though that's certainly another aspect of the challenge—but rather moving genetically. The virus changes its genome quickly, which makes developing drugs to fight it all the more difficult. A drug developed to fight one of the five known Ebola variants might not have much effect against any of the others and, so far, that's all we have in the pipeline: single-strain drugs.

Researchers at the University of Utah have a new study out this week describing a universal Ebola target, a specific region of the virus that is shared among all of the different strains, e.g. it's "conserved." What's more, this region is crucial for the functioning of the virus, consisting of the protein complex used to enter and fuse to a human host cell, thereby initiating an infection.

What the Utah researchers created is, more specifically, a molecule known as a peptide mimic, which is just a lab-created version of the structure that would be found on an actual Ebola virus. This particular peptide mimic is known as GP2, a protein whose role involves the fusion of the virus' outer membrane to that of a human "civilian" cell. Once that fusion occurs, the virus is able to deliver its genetic payload into the human cell, basically creating a new virus factory.

So, current study doesn't present a cure or treatment, but instead gives researchers a more promising and firmly-rooted target. "Viral sequence information from the epidemic reveals rapid changes in the viral genome, while our target sequence remains the same," notes Tracy Clinton, the study's lead author, in a University of Utah statement. "Therefore, our target will enable the discovery of drugs with the potential to treat any future epidemic, even if new Ebola virus strains emerge."

With a peptide target in hand, it should now be much quicker and easier to produce what are known as mirror-image peptide inhibitors (D-peptide). The basic idea is to introduce mirror-images, the D-peptides, of the proteins used by viruses to attach to their cellular prey. The virus should find its GP2 protein, the one used to fuse the virus to its victim, stuck to the D-peptide instead.

"This protein acts like a hairpin, binding to both the human cell and viral membranes in its open state and closing to push these membranes together, causing them to fuse," Michael Kay, the founder of the University of Utah's Kay Lab, told me. "This hairpin closing cannot occur with our D-peptide in the way, like obstructing an animal's jaws with a medicine ball. So the virus still binds to the membrane, but cannot complete [the] fusion process required for cell entry/infection."

The University of Utah team, led by Kay and biochemist Debra Eckert, is in familiar territory. "Our early D-peptide work focused on HIV, but recently we have branched out into developing inhibitors against other viruses that use a similar hairpin closing mechanism of entry," Kay said. "The D-peptides being developed against Ebola are quite different than the earlier anti-HIV D-peptides, but the basic mechanism by which they work, and their discovery methods, are similar to HIV."

In 1999, the group published the first research exploring the D-peptide approach to HIV treatment. Fighting Ebola and HIV and Ebola share some of the same difficulties, particularly the bioavailability of viral inhibitors. Synthetic C-peptides act in a similar way as their d-peptide cousins, binding to the virus's would-be attack vehicle before it can fully attack, but they're quickly broken down by the body, resulting in a need to take lots and lots of it to have any effect.

"Their mechanisms of action are very similar, but the short lifetime of C-peptides has limited their utility," Kay explained. "Interestingly, C-peptides are inactive against Ebola, likely because they do not make it to the endosomal sites of Ebola membrane fusion, either due to degradation or poor transport."

D-peptides, however, have been shown to be strongly resilient to degradation. Using them to fight HIV, at least, would introduce a whole new category into the infection's resistance-prone, and often quite toxic treatment regime.

In collaboration with the Salt Lake City biotech startup Navigen, which holds the license to commercialize D-peptide therapies produced in Kay's lab, the team is working to bring its HIV-fighting D-peptide, known as PIE12-trimer, into the human testing stages. In 2011, it received a $300,000 grant from the US government-funded Small Business Innovation Research program to continue the HIV drug's development. The lofty goal for PIE12-trimer is for it to be an HIV drug that patients can take weekly, rather than the continuous multidrug HAART batteries that are the current standard.

Unfortunately, the Utah team's newest advance won't do much for the current Ebola outbreak. There will be others, however.

"Although the current push of clinical trials will hopefully lead to an effective treatment for the Zaire species causing the present epidemic," Eckert noted, "the same treatments are unlikely to be effective against future outbreaks of a different or new Ebola species. Development of a broadly acting therapy is an important long-term goal that would allow cost-effective stockpiling of a universal Ebola treatment."