RIG-I-Like Receptor Adjuvant Discovery 

 

The RIG-I-Like Receptors and Novel Innate Immune Pathways for Adjuvant Discovery and Development Program is focused on discovering and developing small molecule innate immune adjuvants that target either RIG-I-like receptors (RLRs) and pathways or novel innate immune factors and pathways, with the ultimate goal of enhancing immunity against RNA virus infection. RLRs are a family of cellular RNA helicases that function as innate immune receptors for specific RNA virus ligands. When activated, RLRs stimulate innate and adaptive immune responses against their ligands. By targeting RLRs and their pathways, our goal is to discover and develop adjuvants that override virus countermeasures of RLR signaling; thus serving to stimulate, restore, and enhance innate antiviral immunity against pathogenic RNA viruses. The adjuvants discovered in this program will have the ability to stimulate innate immune pathways and overcome virus countermeasures. Importantly, the identified adjuvants are also likely to display antiviral properties that are independent of an immunogen or vaccination strategy.

Designed as a collaboration based on the research strengths from the Gale and Katze Laboratories at the University of Washington and Kineta Inc., our Research Project is comprised of four research areas:

  • High-Throughput screening: High-throughput screening of small-molecule compound libraries to identify RLR adjuvants and novel cellular factors and pathways that induce innate immunity and immune enhancement.
  • Mechanisms of action: Cell-based biochemical and functional genomics studies to assess the mechanisms of innate immune action of adjuvant compounds and factors identified through high-throughput screening.
  • Lead compound optimization: Lead compound optimization and iterative testing using in vitro and in vivo models linked to biochemical analyses and functional genomic and pathway modeling studies.
  • Preclinical testing: Preclinical testing of lead compounds in vitro and in vivo for adjuvant and antiviral actions against RNA viruses of public health importance, including hepatitis C, respiratory syncytial virus, influenza, and West Nile virus.

In brief, we are using cell-based high-throughput screening platforms to identify compounds that stimulate RLR pathways and innate immunity under conditions of viral evasion of RLR signaling. Validated hits from our screens will be evaluated using a variety of human cell systems and mouse models. For each validated hit, we are exploring the mechanism of action, intracellular points of signaling, innate immune actions, and preclinical efficacy in modulating infection and immunity using molecular, biochemical, virologic, functional genomic, and pathway modeling approaches. To define antiviral potential and the spectrum of activity, candidate adjuvants and innate immune receptors and signaling factors will subsequently be evaluated for activity against other RNA viruses. This approach will result in the discovery, development, and delivery of novel immune adjuvants and cellular factors for antiviral therapeutic and immune enhancement applications.

 

 


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