Circulatory Shock, types and stages, compensatory mechanisms
University of Missouri - Columbia, Broad-Spectrum Antiviral Therapeautics
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. 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. 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. 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. 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. 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. 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. 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. 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. 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
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. 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
