Vemurafenib Limits Influenza A Virus Propagation by Targeting Multiple Signaling Pathways

Abstract

Influenza A viruses (IAV) can cause severe global pandemic outbreaks. The currently licensed antiviral drugs are not very effective and prone to viral resistance. Thus, novel effective and broadly active drugs are urgently needed. We have identified the cellular Raf/MEK/ERK signaling cascade as crucial for IAV replication and suitable target for an antiviral intervention. Since this signaling cascade is aberrantly activated in many human cancers, several clinically approved inhibitors of Raf and MEK are now available. Here we explored the anti-IAV action of the licensed B-RafV600E inhibitor Vemurafenib. Treatment of B-RafWT cells with Vemurafenib induced a hyperactivation of the Raf/MEK/ERK cascade rather than inhibiting its activation upon IAV infection. Despite this hyperactivation, which has also been confirmed by others, Vemurafenib still strongly limited IAV-induced activation of other signaling cascades especially of p38 and JNK mitogen-activated protein kinase (MAPK) pathways. Most interestingly, Vemurafenib inhibited virus-induced apoptosis via impaired expression of apoptosis-inducing cytokines and led to hampered viral protein expression most likely due to the decreased activation of p38 and JNK MAPK. These multiple actions resulted in a profound and broadly active inhibition of viral replication, up to a titer reduction of three orders of a magnitude. Thus, while Vemurafenib did not act similar to MEK inhibitors, it displays strong antiviral properties via a distinct and multi-target mode of action.

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.…”

An active component containing pterodontic acid and pterodondiol isolated from Laggera pterodonta inhibits influenza A virus infection through the TLR7/MyD88/TRAF6/NF‑κB signaling pathway

“…Influenza viruses take advantage of host cellular functions to support efficient viral replication. Numerous studies have reported that cell signaling pathways are involved in the influenza virus life cycle, such as NF-κB (21), Raf/mitogen-activated protein kinase/extracellular signal-regulated kinase (22), phosphatidylinositol 3-kinase/protein kinase B (23) and p38/MAPK (24) pathways. The results of a genome-wide RNA interference screen in mammalian cells revealed that 219 of the 295 factors were identified to be required for efficient wild-type influenza virus replication.…”

Repurposing host-based therapeutics to control coronavirus and influenza virus

“…The B-Raf (V600E) inhibitor vemurafenib, which effectively inhibits the ERK pathway, was approved by the FDA to treat orbital Erdheim-Chester disease (ECD) [88,89]. Vemurafenib, at low micromolar levels, can inhibit IFV-A replication (1000-fold reduction) via suppression of viral translation [90]. Interestingly, vemurafenib also inhibits virus-induced apoptosis in A549 cells via the suppression of apoptosis-inducing cytokines [90].…”

“…Vemurafenib, at low micromolar levels, can inhibit IFV-A replication (1000-fold reduction) via suppression of viral translation [90]. Interestingly, vemurafenib also inhibits virus-induced apoptosis in A549 cells via the suppression of apoptosis-inducing cytokines [90]. Other Raf inhibitors, such as dabrafenib and sorafenib, were FDA-approved to treat cancer.…”