Coronaviruses (CoV) are RNA viruses that cause gastrointestinal, respiratory, and neurological symptoms in several mammalian species. The outbreak of the severe acute respiratory syndrome CoV (SARS-CoV) in humans 2002 was fatal in ~10% of infected patients, infecting ~8000 people and killing 800. The recent incidents involving the highly pathogenic Middle East Respiratory Syndrome CoV (MERS-CoV) demonstrate that the emergence of pathogenic CoVs from animals to humans can occur at any time. There are currently no FDA approved drugs available for treatment of either SARS or MERS; thus, the development of therapeutic agents to treat CoV infections is an essential, unmet medical need. Because entry into host cells is the first step in the viral life cycle, this aea offers a major target for treatment and prevention. CoVs encode three surface proteins, and the spike S protein must be proteolyzed by human cathepsin L (CatL) for proper entry. The fact that several CoVs utilize this key human protease, CatL, for entry offers an opportunity to develop pan-anticoronavirus inhibitor drugs.
We aim to generate potent, specific lead inhibitors for CatL via exploration of the prime side a-helical binding pocket that results in inhibition of SARS-CoV and MERS-CoV infection in live cell assays, and to analyze ADME/toxicology properties en route to testing in animal models of CoV infection.

Public Health Relevance

Coronaviruses cause gastrointestinal, respiratory, and neurological symptoms in humans. The outbreak of the severe acute respiratory syndrome CoV (SARS) in humans 2002 was fatal in ~10% of infected patients, infecting ~8000 people and killing 800. The recent incidents involving the highly pathogenic Middle East Respiratory Syndrome CoV (MERS) demonstrate that the emergence of pathogenic coronaviruses from animals to humans can occur at any time. There are currently no FDA approved drugs available for treatment of either SARS or MERS; thus, the development of therapeutic agents to treat coronavirus infections is an essential, unmet medical need. Both viruses require a human enzyme for the completion of the life cycle. We aim to generate potent, specific lead inhibitors for this enzyme to develop therapeutics for both SARS and MERS infection in people.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Small Business Innovation Research Grants (SBIR) - Phase II (R44)
Project #
1R44AI118063-01
Application #
8905856
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Stemmy, Erik J
Project Start
2015-03-01
Project End
2018-02-28
Budget Start
2015-03-01
Budget End
2016-02-29
Support Year
1
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Phelix Therapeutics, LLC
Department
Type
DUNS #
079291041
City
Philadelphia
State
PA
Country
United States
Zip Code
19104