Network Pharmacology and Bioinformatics Analysis Identifies Potential Therapeutic Targets of Paxlovid Against LUAD/COVID-19

Abstract

BackgroundCoronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused a pandemic in many countries around the world. The virus is highly contagious and has a high fatality rate. Lung adenocarcinoma (LUAD) patients may have higher susceptibility and mortality to COVID-19. While Paxlovid is the first oral drug approved by the U.S. Food and Drug Administration (FDA) for COVID-19, its specific drug mechanism for lung cancer patients infected with COVID-19 remains to be further studied.MethodsCOVID-19 related genes were obtained from NCBI, GeneCards, and KEGG, and then the transcriptome data for LUAD was downloaded from TCGA. The drug targets of Paxlovid were revealed through BATMAN-TCM, DrugBank, SwissTargetPrediction, and TargetNet. The genes related to susceptibility to COVID-19 in LUAD patients were obtained through differential analysis. The interaction of LUAD/COVID-19 related genes was evaluated and displayed by STRING, and a COX risk regression model was established to screen and evaluate the correlation between genes and clinical characteristics. The Venn diagram was drawn to select the candidate targets of Paxlovid against LUAD/COVID-19, and the functional analysis of the target genes was performed using KEGG and GO enrichment analysis. Finally, Cytoscape was used to screen and visualize the Hub Gene, and Autodock was used for molecular docking between the drug and the target.ResultBioinformatics analysis was performed by combining COVID-19-related genes with the gene expression and clinical data of LUAD, including analysis of prognosis-related genes, survival rate, and hub genes screened out by the prognosis model. The key targets of Paxlovid against LUAD/COVID-19 were obtained through network pharmacology, the most important targets include IL6, IL12B, LBP. Furthermore, pathway analysis showed that Paxlovid modulates the IL-17 signaling pathway, the cytokine-cytokine receptor interaction, during LUAD/COVID-19 treatment.ConclusionsBased on bioinformatics and network pharmacology, the prognostic signature of LUAD/COVID-19 patients was screened. And identified the potential therapeutic targets and molecular pathways of Paxlovid Paxlovid in the treatment of LUAD/COVID. As promising features, prognostic signatures and therapeutic targets shed light on improving the personalized management of patients with LUAD.

Oral antivirals for COVID-19 among patients with cancer

“…It should be noted that DDIs between medications that oncologic patients often take and Paxlovid® may signi cantly affect the risk-bene t ratio or even be prohibitive of its administration [12][13][14]. Nirmatrelvir, an antiviral protease inhibitor against SARS-CoV-2, is pharmacokinetically enhanced by ritonavir, a potent CYP3A4 inhibitor, to achieve therapeutic plasma concentrations [25].…”

“…A post hoc analysis from the aforementioned RCT [5] showed that molnupiravir treatment of mild-to-moderate COVID-19 in non-hospitalized, unvaccinated, immunocompromised adults was safe, but the clinical bene t from its administration, although numerically substantial, did not reach statistical signi cance [8,11]. Importantly, adverse effects due to drug-drug interactions (DDI) between medications that immunocompromised patients may already be taking, and nirmatrelvir/ritonavir may impact its tolerability among patients with cancer [12][13][14]. Moreover, recently completed RCTs of both drugs showed a lack of clinical bene t from their use among low-risk patients or even vaccinated high-risk patients in the current era of Omicron variants and widespread immunity to SARS-CoV-2 [15][16][17][18] To our knowledge, no studies to date have speci cally appraised the effectiveness of molnupiravir and nirmatrelvir/ritonavir in preventing hospitalization and mortality, exclusively among patients with solid or hematologic malignancies, using appropriate, concurrent controls.…”

Revealing the role of metformin in gastric intestinal metaplasia treatment

“…Genes targeted by metformin were collected from online databases, including SuperPred ( Ma et al, 2022 ), Pharm Mapper ( Jiao et al, 2022 ), Swiss Target Prediction ( Shang et al, 2023 ), and TargetNet ( Zhang et al, 2022c ), with “metformin” as the keyword. Uniprot database was used to identify the genes.…”