Abstract
BackgroundSimilarities in the hijacking mechanisms used by SARS-CoV-2 and several types of cancer, suggest the repurposing of cancer drugs to treat Covid-19. CK2 kinase antagonists have been proposed for cancer treatment. A recent study in cells infected with SARS-CoV-2 found a significant CK2 kinase activity, and the use of a CK2 inhibitor showed antiviral responses. CIGB-300, originally designed as an anticancer peptide, is an antagonist of CK2 kinase activity that binds to the CK2 phospho-acceptor sites. Recent preliminary results show the antiviral activity of CIGB-300 using a surrogate model of coronavirus. Here we present a computational biology study that provides evidence, at the molecular level, of how CIGB-300 may interfere with the SARS-CoV-2 life cycle within infected human cells.MethodsSequence analyses and data from phosphorylation studies were combined to predict infection-induced molecular mechanisms that can be interfered by CIGB-300. Next, we integrated data from multi-omics studies and data focusing on the antagonistic effect on the CK2 kinase activity of CIGB-300. A combination of network and functional enrichment analyses was used.ResultsFirstly, from the SARS-CoV studies, we inferred the potential incidence of CIGB-300 in SARS-CoV-2 interference on the immune response. Afterwards, from the analysis of multiple omics data, we proposed the action of CIGB-300 from the early stages of viral infections perturbing the virus hijacking of RNA splicing machinery. We also predicted the interference of CIGB-300 in virus-host interactions that are responsible for the high infectivity and the particular immune response to SARS-CoV-2 infection. Furthermore, we provided evidence of how CIGB-300 may participate in the attenuation of phenotypes related to muscle, bleeding, coagulation and respiratory disorders.ConclusionsOur computational analysis proposes putative molecular mechanisms that support the antiviral activity of CIGB-300.
Highlights
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with increasing levels of infectivity and transmissibility, has strained health systemsSince the genomic sequence of SARS-CoV-2 became available in January 2020 (Zhou et al 2020a), a diversityMiranda et al Molecular Medicine (2021) 27:161 of techniques and laboratory models have been applied to study SARS-CoV-2 replication and infectivity.Blanco-Mello et al (2020) performed RNA-seq experiments from polyA RNAs isolated from infected cells
Taking into account all the above mentioned, we suggest that CIGB-300 may interfere in the phosphorylation of Serine and arginine rich splicing factor 1 (SRSF1) by targeting the SRSF protein kinase 1 (SRPK1) kinase
Evaluating how CIGB-300 may interfere in the hosthost protein interactions involved in virus-induced mechanisms, we found that there were 68 proteins with activated phospho-acceptor sites in at least two of the four phosphoproteomic studies, which were inhibited by CIGB300
Summary
The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), with increasing levels of infectivity and transmissibility, has strained health systemsSince the genomic sequence of SARS-CoV-2 became available in January 2020 (Zhou et al 2020a), a diversityMiranda et al Molecular Medicine (2021) 27:161 of techniques and laboratory models have been applied to study SARS-CoV-2 replication and infectivity.Blanco-Mello et al (2020) performed RNA-seq experiments from polyA RNAs isolated from infected cells. The study of Gordon et al (2020) is of outstanding relevance for the understanding of the mechanism used by SARS-CoV-2 to improve its infectivity and to avoid a strong immune response. It provides valuable information for the repurposing of the existing drugs. We present a computational biology study that provides evidence, at the molecular level, of how CIGB-300 may interfere with the SARS-CoV-2 life cycle within infected human cells
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