Protease-resistant D-peptide Inhibitors of Ebola Virus Entry

Award Information
Agency:
Department of Health and Human Services
Branch
n/a
Amount:
$600,000.00
Award Year:
2012
Program:
SBIR
Phase:
Phase I
Contract:
1R43AI102347-01
Agency Tracking Number:
R43AI102347
Solicitation Year:
2012
Solicitation Topic Code:
NIAID
Solicitation Number:
PA11-096
Small Business Information
NAVIGEN, INC.
383 Colorow Drive, SALT LAKE CITY, UT, -
Hubzone Owned:
N
Socially and Economically Disadvantaged:
N
Woman Owned:
N
Duns:
792046224
Principal Investigator:
BRETT WELCH
(801) 587-1415
bwelch@nvgn.com
Business Contact:
BRANDI SIMPSON
(801) 587-1401
bsimpson@nvgn.com
Research Institution:
Stub




Abstract
DESCRIPTION (provided by applicant): 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 averagemortality 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-peptideinhibitor 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 andis 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.

* information listed above is at the time of submission.

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