A small molecule inhibitor of MyD88 exhibits broad spectrum antiviral activity by up regulation of type I interferon

被引：21

作者：

Saikh, Kamal U. ^{[1
]}

Morazzani, Elaine M. ^{[2
]}

Piper, Ashley E. ^{[2
]}

Bakken, Russell R. ^{[2
]}

Glass, Pamela J. ^{[2
]}

机构：

[1] US Army, Dept Bacterial Immunol, Bacteriol Div, Med Res Inst Infect Dis, 1425 Porter St, Frederick, MD 21702 USA

[2] US Army, Div Virol, Med Res Inst Infect Dis, 1425 Porter St, Frederick, MD 21702 USA

来源：

ANTIVIRAL RESEARCH | 2020年 / 181卷

关键词：

Type 1 interferon (IFN-beta); RANTES; MyD88; IRF; TLR3; Poly I:C; VEEV; Ebola virus; EQUINE ENCEPHALITIS-VIRUS; TOLL-LIKE RECEPTORS; ALPHA/BETA INTERFERON; IMMUNE-RESPONSES; PROTECTS MICE; MOUSE MODEL; WILD-TYPE; INFECTION; EBOLA; CELL;

D O I：

10.1016/j.antiviral.2020.104854

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

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-beta and RANTES production. Consistent with these results, overexpression of MyD88 decreased IFN-beta, whereas MyD88 inhibition rescued IFN-beta production concomitant with increased IRF3 phosphorylation, suggesting IRF-mediated downstream signaling to the IFN-beta 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 suppressed replication of VEEV, Eastern equine encephalitis virus, Ebola virus (EBOV), Rift Valley Fever virus, Lassa virus, and Dengue virus with IC50 values ranging from 11 to 42 mu M. Notably, administration of compound 4210 improved survival, weight change, and clinical disease scores in mice following challenge with VEEV TC-83 and EBOV. Collectively, these results provide evidence that viral infections responsive to MyD88 inhibition lead to activation of IRF3/IRF7 and promoted a type I IFN response, thus, raising the prospect of an approach of host-directed antiviral therapy.

引用

页数：16