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U.S. Scientists Develop Universal Ebola Drug Target
Biochemists at the University of Utah have reported a new drug-discovery tool against the Ebola virus. According to a study published online in Protein Science, they have produced a molecule, known as a peptide mimic, that displays a functionally critical region of the virus that is universally conserved in all known species of Ebola. This new tool can be used as a drug target in the discovery of anti-Ebola agents that are effective against all known strains and likely future strains, the researchers say.
The scientists designed peptide mimics of a highly conserved region in the Ebola protein that controls entry of the virus into the human host cell, initiating infection. Importantly, the researchers were able to demonstrate that this peptide target is suitable for use in high-throughput drug screens. These kinds of screens allow rapid identification of potential new drugs from billions of possible candidates.
Current experimental drugs generally target only one of the Ebola virus’ five species.
“The current growing epidemic demonstrates the need for effective broad-range Ebola virus therapies,” said lead author Dr. Tracy R. Clinton. “Importantly, viral sequence information from the epidemic reveals rapid changes in the viral genome, while our target sequence remains the same. Therefore, our target will enable the discovery of drugs with the potential to treat any future epidemic, even if new Ebola virus strains emerge.”
Ebola is a lethal virus that causes severe hemorrhagic fever, with a 50% to 90% mortality rate. Outbreaks have been occurring with increasing frequency in recent years, and an unprecedented and rapidly expanding Ebola outbreak is currently spreading through West Africa with devastating consequences.
The development of an effective anti-Ebola agent to protect against natural outbreaks and potential bio-terror exposures is an urgent global health need, the authors say. There are no approved anti-Ebola agents, but a number of promising experimental drugs are being advanced to clinical trials to address the current crisis.
Eckert noted: “Although the current push of clinical trials will hopefully lead to an effective treatment for the Zaire species causing the present epidemic, 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.”
According to Eckert, this target was shown to be suitable for the discovery of mirror-image peptide inhibitors (D-peptides), which are promising drug candidates. Unlike natural peptides, they are not digested by enzymes in the blood. D-peptides are also much simpler and less expensive to produce compared with the current most-promising approach, antibodies.
The researchers had previously developed potent and broadly acting D-peptide inhibitors of human immunodeficiency virus (HIV) entry, currently in preclinical studies, and are now adapting this approach to Ebola using the mimics developed in the previous study. In collaboration with Navigen Pharmaceuticals, based in Salt Lake City, Utah, the investigators have identified several promising lead D-peptide inhibitors. Additional funding is being sought to optimize these inhibitors and to advance them into clinical trials in human subjects.
Source: University of Utah Health Care; October 7, 2014.