SARS-CoV-2 and the Possible Role of Raf/MEK/ERK Pathway in Viral Survival: Is This a Potential Therapeutic Strategy for COVID-19?

Ghasemnejad‐Berenji, Morteza; Pashapour, Sarvin

doi:10.1159/000511280

Cited by 38 publications

(39 citation statements)

References 26 publications

(29 reference statements)

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“…It has been recently reported that SARS-CoV-2 infection is able to induce a strong up- and downregulation of components of many cellular signaling pathways involved in cancer, including the RAS-RAF/MEK/ERK signaling pathway [ 4 ]. Therefore, it appears likely that the activation of this signaling pathway could be involved in the SARS-CoV-2 virus infection and survival too.…”

Section: Introductionmentioning

confidence: 99%

H-Ras gene takes part to the host immune response to COVID-19

Sciacchitano

Sacconi²,

Vitis

et al. 2021

Cell Death Discov.

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Ras gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19.

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Section: Introductionmentioning

confidence: 99%

H-Ras gene takes part to the host immune response to COVID-19

Sciacchitano

Sacconi²,

Vitis

et al. 2021

Cell Death Discov.

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“…Vemurafenib can disturb the cellular Raf/MEK/ERK signaling cascade via binding in the ATP-binding site of BRAF(V600E) kinase and inhibiting its function [ 61 ], whereas sorafenib is another kinase inhibitor that targets VEGFR, PDGFR, and RAF kinases [ 62 ]. Interestingly, SARS-CoV-1 uses Raf/MEK/ERK signaling pathways to promote its replication via various mechanisms, indicating that this signaling cascade is a critical therapeutic target for host-directed SARS-CoV-2 antivirals [ 63 , 64 , 65 ].…”

Section: Discussionmentioning

confidence: 99%

A COVID-19 Drug Repurposing Strategy through Quantitative Homological Similarities Using a Topological Data Analysis-Based Framework

et al. 2021

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Since its emergence in March 2020, the SARS-CoV-2 global pandemic has produced more than 116 million cases and 2.5 million deaths worldwide. Despite the enormous efforts carried out by the scientific community, no effective treatments have been developed to date. We applied a novel computational pipeline aimed to accelerate the process of identifying drug repurposing candidates which allows us to compare three-dimensional protein structures. Its use in conjunction with two in silico validation strategies (molecular docking and transcriptomic analyses) allowed us to identify a set of potential drug repurposing candidates targeting three viral proteins (3CL viral protease, NSP15 endoribonuclease, and NSP12 RNA-dependent RNA polymerase), which included rutin, dexamethasone, and vemurafenib. This is the first time that a topological data analysis (TDA)-based strategy has been used to compare a massive number of protein structures with the final objective of performing drug repurposing to treat SARS-CoV-2 infection.

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“…5 Moreover, the S protein activates the Raf/MEK/ERK signal transduction pathway in host cells. 4 Manipulation of the host ERK1/2 signalling pathway is reportedly instrumental to viral replication, 4,24 and to the induction of cyclooxygenase-2, a prostaglandin synthetase involved in inflammation. 25 Pharmacological inhibition or knockdown of ERK1/2 by small interfering RNAs suppressed coronavirus replication.…”

Section: Discussionmentioning

confidence: 99%

“…Such binding triggers a cascade of events that leads to fusion of the viral and cellular membranes to facilitate virus entry, 3 and subsequent manipulation of the host Raf/MEK/ERK signalling pathway to regulate viral replication and gene transcription in host cells. 4 The receptor-binding domain (RBD) contained in the S1 subunit of the viral S protein recognizes and binds to the host receptor angiotensin-converting enzyme 2 (ACE2), while the S2 subunit mediates viral -cell membrane fusion by forming a six-helical bundle via the twoheptad repeat domain. 5,6 Interestingly, the recombinant S1 subunit (Val16 -Gln690), but not the S1 subunit (Arg319 -Phe541) that contains the ACE2 RBD, induces MEK phosphorylation in pulmonary vascular cells.…”

Section: Introductionmentioning

confidence: 99%