KIN1408 is a small molecule that targets factors at or above the level of MAVS in the RLR signaling pathway to drive IRF3 activation (IRF3 nuclear translocation ECmax = 5 μM in 20 h; Huh7 cells) without significant cytotoxicity (50 μM/20 h in Huh7 or 20 μM/36 h in HEK293 cultures). KIN1408 induces cellular transcription of innate immune genes (Eff. conc. 1.25-20 μM in 20 h; PMA-differentiated THP-1 cells) in a MAVS- and IRF3-dependent manner and exhibits broad-spectrum anti-viral activity (Eff. conc. 1-5 μM), including dengue virus 2 (DV2; Huh7), influenza A (IAV H3N2; HEK293), RSV (A2 strain; HeLa), Ebola (EBOV strain Zaire; HUVECs), Nipah virus (NiV; HUVECs), and Lassa virus (LASV; HUVECs). MAVS signaling activation upon Zika virus infection or KIN1408 treatment is reported to result in pTBK1 mitochondria relocalization and caspase 3-mediated apoptosis in human neuroepithelial stem (NES) cells.
The mechanisms underlying Zika virus (ZIKV)-related microcephaly and other neurodevelopment defects remain poorly understood. Here, we describe the derivation and characterization, including single-cell RNA-seq, of neocortical and spinal cord neuroepithelial stem (NES) cells to model early human neurodevelopment and ZIKV-related
Journal of virology, 90(5), 2372-2387 (2015-12-18)
The cellular response to virus infection is initiated when pathogen recognition receptors (PRR) engage viral pathogen-associated molecular patterns (PAMPs). This process results in induction of downstream signaling pathways that activate the transcription factor interferon regulatory factor 3 (IRF3). IRF3 plays
The recognition of pathogen associated molecular patterns (PAMPs) by pattern recognition receptors (PRR) during viral infection initiates the induction of antiviral signaling pathways, including activation of the Interferon Regulator Factor 3 (IRF3). We identified small molecule compounds that activate IRF3
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