Small molecule inhibitors for treatment of alpha viruses
| DWPI Title: Pharmaceutical composition for treatment for an alphavirus, Rift Valley Fever infection or Zika virus infection, comprises compound for e.g.,5H-[1,2,4]Triazino[5,6-b]indole-3-thiol and/or 3-methyl-2H,b3H-naphtho[2,1-d][1,3]thiazol-2-imine (IV) or their salts, and excipient |
| 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. |
| Use: Pharmaceutical composition for treatment for an alphavirus, Rift Valley Fever infection or Zika virus infection, where the alphavirus is Chikungunya virus, Venezuelan Equine Encephalitis virus, Sindbis virus, O'nyong-nyong virus, Ross River virus, Barmah Forest virus, Semiliki Forest virus, Eastern equine encephalitis virus (EEEV), or Western equine encephalitis virus (WEEV), the infection is a Chikungunya virus infection, Venezuelan Equine Encephalitis virus infection, or Rift Valley Fever Virus infection.Anti-chikungunya virus (CHIKV) efficacy of candidate compounds in tissue culture screening assays was determined. Small molecule libraries are known to contain a wide-variety of molecule types, including many which that are non-membrane permeable, cytotoxic, non-specific in functionality, or other attributes that may impair anti-viral efficacy in a cellular system. Therefore, the compounds from the screen were assessed for cytotoxicity in cell culture. The result shows compounds (III) and (IV) had the lowest projected IC50 values of 2.82 µM, and 2.59 µM, respectively, while the IC50 of compound (I) was 10.88 µM, and the IC50 of compound (II) was 4.9 µM. |
| Advantage: The composition utilizes small molecules that have the benefit of being cell penetrating, more suitable for oral delivery, and easier to manufacture than protein or other large molecule treatments, shows pan-alphavirus anti-viral efficacy at concentrations that did not result in cell toxicity. |
| Novelty: A pharmaceutical composition comprises a compound selected from (2E)-3-(2H-1,3-benzodioxol-5-yl)-1-(4-{[4-(furan-2-yl)-1,3-thiazol-2-yl]methyl}piperazin-1-yl)prop-2-en-1-one (I), 2-hydroxy-4-[(5Z)-5-[(4-hydroxy-3-methoxyphenyl)methylidene]-4-oxo-2-sulfanylidene-1,3-thiazolidin-3-yl]benzoic acid (II), 5H-[1,2,4]Triazino[5,6-b]indole-3-thiol (III) and/or 3-methyl-2H,b3H-naphtho[2,1-d][1,3]thiazol-2-imine (IV) or their salts, and an excipient, where if compound (III), its salt, or combination is selected, the composition is formulated for oral or parenteral delivery. |
| Filed: 3/2/2021 |
| Application Number: US17189596A |
| Tech ID: SD 14540.0 |
| This invention was made with Government support under Contract No. DE-NA0003525 awarded by the United States Department of Energy/National Nuclear Security Administration. The Government has certain rights in the invention. |
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