Role of p38 mitogen‐activated protein kinase signalling in virus replication and potential for developing broad spectrum antiviral drugs

Abstract

Summary Mitogen‐activated protein kinases (MAPKs) play a key role in complex cellular processes such as proliferation, development, differentiation, transformation and apoptosis. Mammals express at least four distinctly regulated groups of MAPKs which include extracellular signal‐related kinases (ERK)‐1/2, p38 proteins, Jun amino‐terminal kinases (JNK1/2/3) and ERK5. p38 MAPK is activated by a wide range of cellular stresses and modulates activity of several downstream kinases and transcription factors which are involved in regulating cytoskeleton remodeling, cell cycle modulation, inflammation, antiviral response and apoptosis. In viral infections, activation of cell signalling pathways is part of the cellular defense mechanism with the basic aim of inducing an antiviral state. However, viruses can exploit enhanced cell signalling activities to support various stages of their replication cycles. Kinase activity can be inhibited by small molecule chemical inhibitors, so one strategy to develop antiviral drugs is to target these cellular signalling pathways. In this review, we provide an overview on the current understanding of various cellular and viral events regulated by the p38 signalling pathway, with a special emphasis on targeting these events for antiviral drug development which might identify candidates with broad spectrum activity.

hnRNPA1 regulates early translation to replication switch in SARS-CoV-2 life cycle

“…Initially we observed a switch on/off phenomenon in the hnRNPA1 expression levels Inhibitors that block the m6A pathway would target cellular factors (47), therefore the emergence of drug-resistant viral mutants would seem to be unlikely in epidrugs (28,(48)(49)(50)(51)(52)(53)(54)(55). However, since such drugs would also inhibit the epitranscriptomic modification of cellular mRNAs, they may lead to toxicity (48) and should be used for treating the acute infections.…”

S-adenosylmethionine-dependent methyltransferase inhibitor DZNep blocks transcription and translation of SARS-CoV-2 genome with a low tendency to select for drug-resistant viral variants

“…The requirement of the cellular factors is usually conserved among multiple strains of a particular virus or even across multiple members of a given virus family ( Chander et al, 2021 ; Khandelwal et al, 2020 ; Kumar et al, 2011a , 2011b , 2019 ). We demonstrated in vitro antiviral efficacy of DZNep (inhibitor that targets cellular factor-methyl transferase) against both wild-type and Delta strains of SARS-CoV-2, besides demonstrating it's protective effect against lethal IBV ( Coronaviridae family member) infection in embryonated chicken eggs suggesting a broad-spectrum antiviral effect.…”

Triclosan regulates the Nrf2/HO‐1 pathway through the PI3K/Akt/JNK signaling cascade to induce oxidative damage in neurons

“…The PI3K/Akt signaling pathway plays a core role in cell physiology and pathology and participates in key cellular processes, such as glucose homeostasis, lipid metabolism and protein synthesis by mediating growth factor signals 51 . MAPK family members are key kinases involved in most signal transduction pathways, are activated by a wide range of cellular stresses, and regulate the activity of some downstream kinases and transcription factors 52 . A large number of studies have shown that the PI3K/Akt and MAPK signaling pathways, upstream of Nrf2, are also involved in the activation of the Nrf2 pathway.…”