Production of IFNa is one of the earliest host immune responses after viral infection. The fundamental importance of this Type I interferon, lies in its ability to induce downstream activation of both innate and adaptive immune cells via direct and indirect mechanisms. Because they promote potent anti-viral activity, Type I IFNs have been used as both a monotherapy and in combination with other small molecules for enhanced efficacy in the treatment of chronic viral infections, such as Hepatitis C. Despite the fact that only a portion of patients respond to treatment, and that adverse side-effects from long term dosing regimens are a significant barrier, IFNs remain the best standard of care. Thus, it is the overall goal of this project to develop, in parallel, two classes of IFNa enhancers, one protein and the other small molecule, that may be used alone or in combination with other therapeutics for the broad-spectrum treatment of viral infections. First, in an effort to improve functional responses to IFNs and reduce their toxicity, the Garcia group has developed an approach to re-engineer and expand the menu of existing IFNs with recombinant proteins that exhibit superior therapeutic properties. This method, known as in vitro evolution, has been previously and successfully employed by the Garcia group to engineer cytokines with unique structure-activity relationships and that have proven to be more efficacious than the natural cytokine. Second, the Khosia group will pursue chemical biological studies on a recently discovered polyketide natural product, A-74528, that has been found to enhance the antirviral effects of IFNa. The Khosia group will also engage in production and biochemical and structural analysis of A-74528 analogs.
In Aim 1 we will engineer and improve IFN antiviral activities using in vitro evolution to create IFNs with altered affinity or dimerization geometries with the receptor complex.
In Aim 2 we will conduct biophysical studies of candidate IFNs to determine their mechanisms of action, as monotherapies or in combination with other therapeutics.
In Aim 3 we will investigate the inhibitory mechanism and pharmacological properties of A- 74528 through kinetic and dose-response analyses.
In Aim 4 we will design and synthesize analogs of A- 74528 to define structure activity relationships. This unique interfacing of protein and small molecule medicinal chemistry will hopefully yield highly granular, predictive structure-activity metrics linking the molecular and mechanistic parameters of IFN action to antiviral function.

Public Health Relevance

Type I interferons (IFNs) are important for immunity to many types of viral pathogens. They bolster host immunity by helping to activate immune cells and promoting the production of other antiviral proteins to prevent replication and spread of the virus. IFNs have met with limited success as drugs for treating viral diseases, but still often are a patient's best option. Our goal is to engineer an expanded class of improved IFN drugs, and small molecule IFN-enhancers that will be used to treat a broad variety of viral infections.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
1U19AI109662-01
Application #
8643869
Study Section
Special Emphasis Panel (ZAI1-LR-M (J1))
Project Start
2014-04-10
Project End
2019-03-31
Budget Start
2014-04-10
Budget End
2015-03-31
Support Year
1
Fiscal Year
2014
Total Cost
$484,317
Indirect Cost
$164,789
Name
Stanford University
Department
Type
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Schor, Stanford; Einav, Shirit (2018) Combating Intracellular Pathogens with Repurposed Host-Targeted Drugs. ACS Infect Dis 4:88-92
Sweeney, Timothy E; Wynn, James L; Cernada, MarĂ­a et al. (2018) Validation of the Sepsis MetaScore for Diagnosis of Neonatal Sepsis. J Pediatric Infect Dis Soc 7:129-135
Wu, Zhenqin; Ramsundar, Bharath; Feinberg, Evan N et al. (2018) MoleculeNet: a benchmark for molecular machine learning. Chem Sci 9:513-530
Dudek, Amanda M; Pillay, Sirika; Puschnik, Andreas S et al. (2018) An Alternate Route for Adeno-associated Virus (AAV) Entry Independent of AAV Receptor. J Virol 92:
Gee, Marvin H; Han, Arnold; Lofgren, Shane M et al. (2018) Antigen Identification for Orphan T Cell Receptors Expressed on Tumor-Infiltrating Lymphocytes. Cell 172:549-563.e16
Barouch-Bentov, Rina; Einav, Shirit (2018) Turning Up Your Nose for a Flaviviral Encephalitis Cure. Cell Host Microbe 23:427-429
Rinis, Natalia; Golden, Jennifer E; Marceau, Caleb D et al. (2018) Editing N-Glycan Site Occupancy with Small-Molecule Oligosaccharyltransferase Inhibitors. Cell Chem Biol 25:1231-1241.e4
Constant, David A; Mateo, Roberto; Nagamine, Claude M et al. (2018) Targeting intramolecular proteinase NS2B/3 cleavages for trans-dominant inhibition of dengue virus. Proc Natl Acad Sci U S A 115:10136-10141
Vallania, Francesco; Tam, Andrew; Lofgren, Shane et al. (2018) Leveraging heterogeneity across multiple datasets increases cell-mixture deconvolution accuracy and reduces biological and technical biases. Nat Commun 9:4735
Bongen, Erika; Vallania, Francesco; Utz, Paul J et al. (2018) KLRD1-expressing natural killer cells predict influenza susceptibility. Genome Med 10:45

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