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University of Missouri - Columbia, Broad-Spectrum Antiviral Therapeautics

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Broad-Spectrum Antiviral Therapeautics Targeting S1P-Metabolizing Enzymes presented for Whiteboard2Boardroom on December 11, 2018

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University of Missouri - Columbia, Broad-Spectrum Antiviral Therapeautics

  1. 1. Broad-Spectrum Antiviral Therapeutics Targeting S1P-Metabolizing Enzymes Presentation by: Brian Buntaine, M.S., M.B.A. Sr. Licensing Associate Office of Tech. Mgmt & Industry Relations Research by: Bumsuk Hahm, Ph.D. Associate Professor Molecular Microbiology and Immunology
  2. 2. Viral Infections Affect Human Health Globally • Influenza kills an average of 250K – 500K each year • Rare strains have potential to kill many more • The 1918 global influenza pandemic infected ~500M and killed ~50M Illustration from https://www.cdc.gov/features/1918-flu-pandemic/index.html While vaccines can be made for each new viral variant, new therapeutics can aid in rapid treatment and outbreak prevention. Broader acting viral treatments also have applications in treating common viral infections.
  3. 3. Sphingosine 1-Phosphate (S1P) and Viral Infection • S1P is a blood borne sphingolipid involved in a diversity of cell processes, mostly in the vascular and immune systems • Key regulators of cell death, differentiation, and host immune system Sphingosine 1-Phosphate is an effective target for viral therapeutics • S1P is generated by Sphingosine Kinase (SK) and processed by S1P Lyase (SPL) • S1P has been shown to affect Type I IFN expression, which in turn is known to play a role in host immune response to viral infections Sphingosine Sphingosine 1- Phosphate (S1P) Phospoethanolamine + Hexadecenal Sphingosine Kinase (SK) S1P Lyase (SPL) Viral Replication
  4. 4. Sphingosine Kinase & IAV Positive Feedback Loop - Seo et al. (2013). Sphingosine kinase 1 serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection. PLOS One: 8(8) - Xia et al. (2018). Transient inhibition of sphingosine kinase confers protection to influenza A virus infected mice. Antiviral Research, 158: 171-177 Influenza A (IAV) infection upregulates SK1 level and activation (HEK293 and A549 culture) Sphingosine Kinase 2 (SphK2) overexpression upregulates [IAV] (A549 culture)
  5. 5. Sphingosine Kinase Inhibition Decreases IAV Replication Seo et al. (2013). Sphingosine kinase 1 serves as a pro-viral factor by regulating viral RNA synthesis and nuclear export of viral ribonucleoprotein complex upon influenza virus infection. PLOS One: 8(8) SK inhibition suppresses IAV protein expression (MDCK, A549, HEK293, and NCI-H358 culture); viral [RNA] reduced as well (data not shown) SK inhibition reduces IAV production in a dose- dependent manner (MDCK culture)
  6. 6. Sphingosine Kinase Affects Measles Virus Similarly Vijayan et al. (2014). Sphingosine kinase 1 regulates measles virus replication. Virology 0: 55-63 SK1 overexpression upregulates measles virus (MV) infection (HEK293 culture) SK inhibition suppresses MV protein expression (B95- 8 and H358 culture); DMS also confirmed (data not shown) SK inhibition reduced MV as measured by flow cytometry against cell-surface MV proteins (B95-8 culture)
  7. 7. S1P Lyase (SPL) Inhibits Viral Replication Vijayan et al. (2017). Sphingosine 1-phosphate lyase enhances the activation of IKK ε to promote type I IFN-mediated innate immune responses to influenza A virus infection. J Immunol; 199: 677-687 Transient SPL overexpression decreases viral protein expression CRISPR-Cas9-mediated SPL deletion increases viral protein production CRISPR-Cas9-mediated SPL deletion increases viral titer
  8. 8. Oral SK2 Inhibitor Protects Mice from Influenza A Xia et al. (2018). Transient inhibition of sphingosine kinase confers protection to influenza A virus infected mice. Antiviral Research, 158: 171-177 Oral administration of SK2 inhibitor ABC decreases IAV- fatality Oral administration of SK2 inhibitor ABC decreases IAV-induced weight loss Lungs from treated mice contained lower levels of IAV
  9. 9. Intranasal SK1 Inhibitor Protects Mice from Influenza A Xia et al. (2018). Transient inhibition of sphingosine kinase confers protection to influenza A virus infected mice. Antiviral Research, 158: 171-177 Intranasal administration of SK1 inhibitor SK1-I decreases IAV-fatality
  10. 10. Intranasal Pan SK Inhibitor Protects Mice from Influenza A Xia et al. (2018). Transient inhibition of sphingosine kinase confers protection to influenza A virus infected mice. Antiviral Research, 158: 171-177 Intranasal administration of SK1/SK2 inhibitor DMS decreases IAV-fatality Intranasal administration of SK1/SK2 inhibitor SKI-II decreases IAV-fatality Lungs from treated mice contained lower levels of IAV
  11. 11. S1P-Metabolizing Enzymes for Broad Antiviral Therapy Sphingosine Sphingosine 1- Phosphate (S1P) Phospoethanolamine + Hexadecenal Sphingosine Kinase S1P Lyase (SPL) Viral Replication Therapeutic Strategy Inhibition (DMS, SK-I, SK-II, ABC, or other) Upregulation Sphingosine Sphingosine 1- Phosphate (S1P) Phospoethanolamine + Hexadecenal Sphingosine Kinase S1P Lyase (SPL) Viral Replication Sphingosine Sphingosine 1- Phosphate (S1P) Phospoethanolamine + Hexadecenal Sphingosine Kinase S1P Lyase (SPL) Viral Replication
  12. 12. Intellectual Property Patented technology: • Issued US patent 9,687,477 • Broad claims granted covering compositions and methods of use for sphingosine 1-phosphate modulators in the treatment of viral infections
  13. 13. Partnering Seeking: • Licensing • Sponsored Research • Collaboration Next Steps: • Additional viral strains • Optimize dosing regimen • Novel inhibitors • Mechanistic studies Contact: Jim Baxendale, Director of Whiteboard2Boardroom baxendalej@umkc.edu Brian Buntaine, M.S., M.B.A. Sr. Licensing and Business Development Associate Office of Technology Licensing and Industry Relations University of Missouri-Columbia Phone: 573-882-0470 buntaineb@missouri.edu

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