Format

Send to

Choose Destination
See comment in PubMed Commons below
PLoS Pathog. 2014 Jun 26;10(6):e1004213. doi: 10.1371/journal.ppat.1004213. eCollection 2014 Jun.

Discovery of a novel compound with anti-venezuelan equine encephalitis virus activity that targets the nonstructural protein 2.

Author information

1
Departments of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, United States of America; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, United States of America.
2
Departments of Microbiology and Immunology, University of Louisville, Louisville, Kentucky, United States of America; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, United States of America; Department of Pharmacology and Toxicology, University of Louisville, Louisville, Kentucky, United States of America.
3
Drug Discovery Department, Southern Research Institute, Birmingham, Alabama, United States of America.
4
Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, Kentucky, United States of America.
5
University of Kansas Specialized Chemistry Center, Lawrence, Kansas, United States of America.
6
The United States Army Medical Research Institute for Infectious Diseases, Ft. Detrick, Maryland, United States of America.
7
Institute for Antiviral Research, Utah State University, Logan, Utah, United States of America.
8
Boston University, Boston, Massachusetts, United States of America.
9
Texas Biomedical Research Institute, San Antonio, Texas, United States of America.

Abstract

Alphaviruses present serious health threats as emerging and re-emerging viruses. Venezuelan equine encephalitis virus (VEEV), a New World alphavirus, can cause encephalitis in humans and horses, but there are no therapeutics for treatment. To date, compounds reported as anti-VEEV or anti-alphavirus inhibitors have shown moderate activity. To discover new classes of anti-VEEV inhibitors with novel viral targets, we used a high-throughput screen based on the measurement of cell protection from live VEEV TC-83-induced cytopathic effect to screen a 340,000 compound library. Of those, we identified five novel anti-VEEV compounds and chose a quinazolinone compound, CID15997213 (IC50 = 0.84 µM), for further characterization. The antiviral effect of CID15997213 was alphavirus-specific, inhibiting VEEV and Western equine encephalitis virus, but not Eastern equine encephalitis virus. In vitro assays confirmed inhibition of viral RNA, protein, and progeny synthesis. No antiviral activity was detected against a select group of RNA viruses. We found mutations conferring the resistance to the compound in the N-terminal domain of nsP2 and confirmed the target residues using a reverse genetic approach. Time of addition studies showed that the compound inhibits the middle stage of replication when viral genome replication is most active. In mice, the compound showed complete protection from lethal VEEV disease at 50 mg/kg/day. Collectively, these results reveal a potent anti-VEEV compound that uniquely targets the viral nsP2 N-terminal domain. While the function of nsP2 has yet to be characterized, our studies suggest that the protein might play a critical role in viral replication, and further, may represent an innovative opportunity to develop therapeutic interventions for alphavirus infection.

PMID:
24967809
PMCID:
PMC4072787
DOI:
10.1371/journal.ppat.1004213
[Indexed for MEDLINE]
Free PMC Article
PubMed Commons home

PubMed Commons

0 comments
How to join PubMed Commons

    Supplemental Content

    Full text links

    Icon for Public Library of Science Icon for PubMed Central
    Loading ...
    Support Center