The c-Jun N-terminal kinase inhibitor SP600125 inhibits human cytomegalovirus replication

Abstract

Human cytomegalovirus (HCMV) is an opportunistic pathogen that causes severe diseases in congenitally infected newborns and immunocompromised patients. Currently, no vaccine is available to prevent HCMV infection. Anti-viral drugs are limited by their side effects and drug resistance. In this study, by performing a medium-sized, anti-HCMV chemical screening, we identified SP600125, CC-401, and the c-Jun N-terminal kinase (JNK) inhibitor VIII, three structurally different small molecule JNK inhibitors that effectively inhibited HCMV replication in cultured human fibroblasts (HFs). SP600125 showed its potential by inhibiting the viral replication of a HCMV laboratory strain in HFs and a HCMV clinical strain in human retinal pigment epithelial cells. Knockdown of JNK expression by RNA interference significantly impaired HCMV replication, mimicking the effect of the chemical inhibitors on virus infection. Mechanistically, SP600125 affects a very early step of the viral life cycle. Viral binding, entry, and the delivery of viral DNA into the cells were not inhibited by the compound. Instead, it suppressed the transcription of the immediate-early viral genes IE1/2 and the accumulation of their gene products. IE1/2 are among the first genes expressed after viral entry, and they are the master regulators of late phase viral gene expression. Consistent with this notion, the expression of other viral genes was also reduced after SP600125 treatment. We propose that JNK inhibitors have the potential to become a new class of anti-HCMV drug candidates, and JNK is a feasible target for the development of anti-HCMV drugs.

Role of MAPK/MNK1 signaling in virus replication

“…Classically, antiviral agents are developed by targeting certain viral components. Viral genome is highly unstable and undergoes frequent mutations; under selection pressure of a drug, virus quickly acquires (Reeves et al, 2005(Reeves et al, , 2011 EGFR Gefitinib (Iressa) Poxvirus and HCMV (Herget et al, 2004;Langhammer et al, 2011) NGFR AG879 IAV, Sendai virus, HSV-1, MHV, and rotavirus (Kumar et al, 2011a, b) PDGFR Tyrphostin A9 (A9) IAV, Sendai virus, HSV-1, MHV, and rotavirus (Kumar et al, 2011a, b) Src family kinases TG100572 HSV-1 (Sharma et al, 2011) Raf (MAP3K) Vemurafenib IAV (Holzberg et al, 2017) MEK1/2 (MAP2K) U0126 IAV, IAB, PEDV, Astrovirus, BDV, Coronavirus, JUNV and HSV-1 (Cai et al, 2007;Colao et al, 2017;Kim and Lee, 2015;Ludwig et al, 2004;Moser and Schultz-Cherry, 2008;Planz et al, 2001;Rodriguez et al, 2014 (Borgeling et al, 2014;Chulu et al, 2010;Hirasawa et al, 2003) JNK (MAPK) AS601245 IAV (Nacken et al, 2012) SP600125 IAV and HCMV (Nacken et al, 2012;Zhang et al, 2015) MNK1 CGP57380 HSV-1, Poxvirus and HCMV (Walsh et al, 2008;Walsh and Mohr, 2004;Walsh et al, 2005) drug resistance at druggable sites. After the advent of high throughput genome sequencing and genome-wide siRNA screens, thousands of cellular factors that support virus replication have been identified.…”

JNK signaling in cancer cell survival

“…Yang and Yao showed that matrine activates the JNK‐Bcl‐2/Bcl‐xL/Bax pathway, which inhibits autophagy through beclin 1, thereby mediating the crosstalk between autophagy and apoptosis. JNK is involved in curcumin‐induced apoptosis and autophagy in osteosarcoma MG63 cells . Moreover, autophagy is important for the resistance to apoptosis in osteosarcoma MG63 cells exposed to curcumin.…”

“…JNK is involved in curcumin-induced apoptosis and autophagy in osteosarcoma MG63 cells. 111 Moreover, autophagy is important for the resistance to apoptosis in osteosarcoma MG63 cells exposed to curcumin. Therefore, autophagy counteracts JNK-induced apoptosis, modulating cancer cell survival and cell death.…”

Hsa-let-7c-5p augments enterovirus 71 replication through viral subversion of cell signaling in rhabdomyosarcoma cells

“…The JNK pathway has been implicated in multiple diseases, including infectious diseases [48]. The JNK pathway has been shown to be required for the viral replication of herpes simplex virus, hepatitis B virus, hepatitis C virus, rotavirus, HIV-1 and human cytomegalovirus [49–54]. In addition, EV71 infection has been reported to activate the JNK pathway in immature dendritic cells and to promote the production of inflammatory cytokines, such as IL-6, IL-10 and TNF-α, whereas inhibition of this pathway results in the suppression of viral replication and the reduced secretion of cytokines [55].…”