Ebola virus (EboV) is a filovirus that causes a highly deadly hemorrhagic fever in humans and non-human primates. Since its discovery in central Africa in 1976, there have been 16 natural human outbreaks with an average mortality rate of 67%. There are no approved agents to prevent or treat Ebola infection. Due to Ebola's ease of dissemination, high lethality, and ability to cause widespread panic, the CDC defines it as a Category A bioterror agent, their category of highest concern. There is great need for an effective EboV preventative and/or treatment, both to combat natural outbreaks as well as for stockpiling for a potential bioterror attack. This project describes an innovative strategy to identify novel D-peptide drug candidates to combat Ebola. D-peptides, the mirror images of natural L-peptides, cannot be digested by proteases and, therefore, have significant therapeutic potential for long in vivo half-lives and reduced immunogenicity. As peptides, they can readily disrupt """"""""undruggable"""""""" large protein/protein interfaces with high potency and specificity (a rare trait for small molecule inhibitors). Navigen's drug discovery platform employs an enantiomeric screening technology (mirror-image phage display) coupled with protein design, to identify D-peptides that stop viruses as they attempt to enter cells. This platform technology has been successfully validated by identifying a promising anti-HIV preclinical candidate, which is the most specific and potent D-peptide inhibitor known. Navigen's anti-HIV D-peptide targets a conserved region found on the HIV envelope protein, the N-trimer, which is transiently exposed during viral entry. It inhibits all major circulating HIV-1 strains and, by design, possesses an extremely high barrier to resistance. Ebola uses a highly similar mechanism of viral entry, and an analogous vulnerable N-trimer has been identified on the Ebola viral surface. This N-trimer will be the target for Navigen's discovery efforts. In this two-year Phase I SBIR, Navigen proposes to identify and structurally characterize D-peptides that potently inhibit Ebola virus. In Phase II, inhibitor optimization will be completed and the resulting D-peptide will be advanced to in vivo efficacy and toxicity studies.

Public Health Relevance

Ebola virus is the causative agent of a highly deadly hemorrhagic fever for which there are no approved therapeutics or preventatives. It has been responsible for numerous natural outbreaks in Africa since the 1970's and is a serious risk as a potential bioterror agent (Category A, CDC). Navigen is developing a potent and novel inhibitor of Ebola infection, which will address the unmet needs of the natural patient population and for stockpiles to combat a bioterror attack.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Small Business Innovation Research Grants (SBIR) - Phase I (R43)
Project #
Application #
Study Section
Special Emphasis Panel (ZRG1-IDM-U (10))
Program Officer
Tseng, Christopher K
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Navigen, Inc.
Salt Lake City
United States
Zip Code
Jacobsen, Michael T; Erickson, Patrick W; Kay, Michael S (2017) Aligator: A computational tool for optimizing total chemical synthesis of large proteins. Bioorg Med Chem 25:4946-4952
Jacobsen, Michael T; Petersen, Mark E; Ye, Xiang et al. (2016) A Helping Hand to Overcome Solubility Challenges in Chemical Protein Synthesis. J Am Chem Soc 138:11775-82
Clinton, Tracy R; Weinstock, Matthew T; Jacobsen, Michael T et al. (2015) Design and characterization of ebolavirus GP prehairpin intermediate mimics as drug targets. Protein Sci 24:446-63
Weinstock, Matthew T; Jacobsen, Michael T; Kay, Michael S (2014) Synthesis and folding of a mirror-image enzyme reveals ambidextrous chaperone activity. Proc Natl Acad Sci U S A 111:11679-84