A small molecule inhibitor of MyD88 exhibits broad spectrum antiviral activity by up regulation of Type I Interferon.

A small molecule inhibitor of MyD88 exhibits broad spectrum antiviral activity by up regulation of Type I Interferon. Antiviral Res. 2020 Jul 01;:104854 Authors: Saikh KU, Morazzani EM, Piper AE, Bakken RR, Glass PJ Abstract Recent studies highlight that infection with Coxsackievirus B3, Venezuelan equine encephalitis virus (VEEV), Marburg virus, or stimulation using poly I:C (dsRNA), upregulates the signaling adaptor protein MyD88 and impairs the host antiviral type I interferon (IFN) responses. In contrast, MyD88 deficiency (MyD88-/-) increases the type I IFN and survivability of mice implying that MyD88 up regulation limits the type I IFN response. Reasoning that MyD88 inhibition in a virus-like manner may increase type I IFN responses, our studies revealed lipopolysaccharide stimulation of U937 cells or poly I:C stimulation of HEK293-TLR3, THP1 or U87 cells in the presence of a previously reported MyD88 inhibitor (compound 4210) augmented IFN-β and RANTES production. Consistent with these results, overexpression of MyD88 decreased IFN-β, whereas MyD88 inhibition rescued IFN-β production concomitant with increased IRF3 phosphorylation, suggesting IRF-mediated downstream signaling to the IFN-β response. Further, compound 4210 treatment inhibited MyD88 interaction with IRF3/IRF7 indicating that MyD88 restricts type I IFN signaling through sequestration of IRF3/IRF7. In cell based infection assays, compound 4210 treatment suppres...
Source: Antiviral Research - Category: Virology Authors: Tags: Antiviral Res Source Type: research