Small molecule inhibitors for treatment of alpha viruses
Abstract
An in vitro assay was designed to measure the activity of the alphavirus non-structural protein 2 (nsP2), which is the viral protease and is required for viral replication. By taking advantage of fluorescence-resonance energy transfer between two proteins, a protease cleavage assay was generated. This was utilized for high-throughput screening of 40,000 small molecules. Inhibitors were validated using cell-based assays to measure alphavirus infection and cytotoxicity. Certain compounds were then characterized for anti-viral efficacy in various cell lines in numerous assays. Compounds were tested against Chikungunya virus, Venezuelan Equine Encephalitis virus, Rift Valley Fever virus, and Zika virus. Three compounds (compounds I, II, and III) showed pan-alphavirus anti-viral efficacy at concentrations that did not result in cell toxicity. An additional compound, structure IV, showed broad spectrum inhibition of all viruses tested. Pharmaceutical preparations and methods of treatment including these compounds are provided herein.
- Inventors:
- Issue Date:
- Research Org.:
- Sandia National Lab. (SNL-CA), Livermore, CA (United States)
- Sponsoring Org.:
- USDOE National Nuclear Security Administration (NNSA)
- OSTI Identifier:
- 1987093
- Patent Number(s):
- 11564919
- Application Number:
- 17/189,596
- Assignee:
- National Technology & Engineering Solutions of Sandia, LLC (Albuquerque, NM)
- Patent Classifications (CPCs):
-
A - HUMAN NECESSITIES A61 - MEDICAL OR VETERINARY SCIENCE A61K - PREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
A - HUMAN NECESSITIES A61 - MEDICAL OR VETERINARY SCIENCE A61P - SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- DOE Contract Number:
- NA0003525
- Resource Type:
- Patent
- Resource Relation:
- Patent File Date: 03/02/2021
- Country of Publication:
- United States
- Language:
- English
- Subject:
- 60 APPLIED LIFE SCIENCES
Citation Formats
Harmon, Brooke Nicole, Negrete, Oscar, Schoeniger, Joseph S., and Saada, Edwin A. Small molecule inhibitors for treatment of alpha viruses. United States: N. p., 2023.
Web.
Harmon, Brooke Nicole, Negrete, Oscar, Schoeniger, Joseph S., & Saada, Edwin A. Small molecule inhibitors for treatment of alpha viruses. United States.
Harmon, Brooke Nicole, Negrete, Oscar, Schoeniger, Joseph S., and Saada, Edwin A. Tue .
"Small molecule inhibitors for treatment of alpha viruses". United States. https://www.osti.gov/servlets/purl/1987093.
@article{osti_1987093,
title = {Small molecule inhibitors for treatment of alpha viruses},
author = {Harmon, Brooke Nicole and Negrete, Oscar and Schoeniger, Joseph S. and Saada, Edwin A.},
abstractNote = {An in vitro assay was designed to measure the activity of the alphavirus non-structural protein 2 (nsP2), which is the viral protease and is required for viral replication. By taking advantage of fluorescence-resonance energy transfer between two proteins, a protease cleavage assay was generated. This was utilized for high-throughput screening of 40,000 small molecules. Inhibitors were validated using cell-based assays to measure alphavirus infection and cytotoxicity. Certain compounds were then characterized for anti-viral efficacy in various cell lines in numerous assays. Compounds were tested against Chikungunya virus, Venezuelan Equine Encephalitis virus, Rift Valley Fever virus, and Zika virus. Three compounds (compounds I, II, and III) showed pan-alphavirus anti-viral efficacy at concentrations that did not result in cell toxicity. An additional compound, structure IV, showed broad spectrum inhibition of all viruses tested. Pharmaceutical preparations and methods of treatment including these compounds are provided herein.},
doi = {},
journal = {},
number = ,
volume = ,
place = {United States},
year = {2023},
month = {1}
}
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