Myeloid differentiation primary response protein 88 (MyD88) plays a critical role in the activation of the host pattern recognition receptors, Toll-like receptors (TLRs), and induction of host pro-inflammatory response. There exists, however, a fine line between beneficial and harmful effects of inflammation, and certain infections and diseases may be facilitated or exacerbated by a pro-inflammatory environment.
Researchers at the U.S. Army Medical Research Institute for Infectious Diseases (USAMRIID) and Scripps Research Institute have developed a novel small molecule compound (known as 4210) that effectively blocks MyD88 signaling. In studies, the compound reduced 3 to 4 log the Eastern Equine Encephalitis Virus (EEEV) and Venezuelan Equine Encephalitis Virus (VEEV) replication in infected U87 cells. In addition, 4210 blocked MyD88-mediated pro-inflammatory signaling and protected mice from toxic shock induced death upon lethal exposure to staphylococcal enterotoxin B (SEB). Although initial research has focused on mitigation and treatment of viral and bacterial infections, 4210 has potential application for other disease states dependent on MyD88-dependent pro-inflammatory signaling.
- Potential application for treatment or mitigation various disease states facilitated or exacerbated by MyD88-dependent pro-inflammatory signaling
- 4210, treats encephalitic alpha virus infections, and gram positive toxic shock
- Inhibition of MyD88 promotes the host anti-viral immune response through TLR3
- 4210 inhibits inflammatory cytokine production in human primary cells and therapeutic efficacy in mice with exposure to toxins of both Gram-positive and Gram-negative pathogens
- 4210 appears to be effective in inhibiting pro-inflammatory response to endotoxin exposure of Gram-negative pathogens, such as F. tularensis, E. coli, or B. mallei, in primary cultures of mice and humans
- 4210 was found to be effective in limiting pro-inflammatory response to both endotoxin and enterotoxin exposure
- US patent 9,833,437 available for license