118: Small molecule RIG-I agonists as vaccine adjuvants and antiviral therapy

Abstract

RIG-I is a pathogen recognition receptor that upon RNA virus infections serves to trigger innate immunity to program the adaptive immune response and is essential for the control of infection. RIG-I signaling initiates antiviral programs that restrict virus infection and activate many cell types including dendritic cells and macrophages for antigen presentation and cytokine production. To develop novel small molecule immune adjuvants, we conducted a high-throughput screen to identify RIG-I agonist molecules from which we derived a lead compound, KIN1148. KIN1148 associates with and activates recombinant RIG-I protein in cell-free assays. Binding to endogenous RIG-I in whole cell extracts promoted KIN1148 association with known RIG-I signaling partners including TRIM25, 14-3-3e, DHX15, TBK1 and NEMO and their assembly on the MAVS adaptor protein. Genomics analyses revealed that KIN1148 activation of RIG-I promotes an IRF3- and NF-kB-dependent transcriptional signature that features the expression of innate immune genes, chemokines and cytokines including CCL2, CCL3, CCL4, CCL7, CXCL10, IL-1b and IL-8 from macrophage-like THP-1 cells and in vivo in mouse tissues. KIN1148 treatment promoted the maturation of primary human dendritic cells to enhance antigen-driven activation of CD8 + T cells in cell culture models. Importantly, when administered to mice in combination with either an experimental influenza A virus or West Nile virus vaccine, KIN1148 enhanced the humoral immune response and protection of mice over vaccine alone in subsequent virus challenge. Thus, we have identified a novel small molecule RIG-I agonist that activates the innate immune response to promote enhanced vaccine immunity against RNA viruses. In parallel work, we have identified a distinct family of compounds that exhibit potent antiviral activity against a broad range of RNA viruses including West Nile, hepatitis C and dengue viruses. Collectively, our work demonstrates the strong potential for developing small molecule agonists that activate RIG-like receptor signaling for prophylactic and therapeutic control of pathogenic RNA viruses. This work is supported by funding from NIH/NIAID ( HHSN272200900035C , HHSN272201300023C and 1R01AI098943 ).