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Small molecule inhibitors for treatment of alpha viruses

Patent ·
OSTI ID:1987093
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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.
Research Organization:
Sandia National Laboratories (SNL-CA), Livermore, CA (United States)
Sponsoring Organization:
USDOE National Nuclear Security Administration (NNSA)
DOE Contract Number:
NA0003525
Assignee:
National Technology & Engineering Solutions of Sandia, LLC (Albuquerque, NM)
Patent Number(s):
11,564,919
Application Number:
17/189,596
OSTI ID:
1987093
Country of Publication:
United States
Language:
English

References (8)

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UCLA’s Molecular Screening Shared Resource: Enhancing Small Molecule Discovery with Functional Genomics and New Technology journal April 2014
Discovery of small molecule inhibitors of chikungunya virus proteins (nsP2 and E1) using in silico approaches journal March 2020
Identification of chikungunya virus nsP2 protease inhibitors using structure-base approaches journal April 2015
A perspective on targeting non-structural proteins to combat neglected tropical diseases: Dengue, West Nile and Chikungunya viruses journal November 2014

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