Underlying Mechanisms and Candidate Drugs for COVID-19 Based on the Connectivity Map Database

Abstract

Background: The coronavirus disease 2019 (COVID-19) has become a worldwide public health crisis. At present, there are no effective antiviral drugs to treat COVID-19. Although some vaccines have been developed, late-stage clinical trials that allow licensure by regulatory agencies are still needed. Previous reports have indicated that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV are highly homologous and both use angiotensin-converting enzyme 2 (ACE2) as the receptor to enter cells, and SARS-CoV infection reduces the ACE2 expression in the lung. Therefore, the analysis of genes co-expressed with ACE2 in the lung may uncover the underlying mechanism of COVID-19. Finally, we used the Connectivity map (Cmap) database to search for candidate drugs using transcriptome profiles of patients with COVID-19. Method: Based on the differentially expressed genes (DEGs), indicated by the expression of RNAs isolated from bronchoalveolar lavage fluid (BALF) cells of patients with COVID-19, we performed functional enrichment analysis and hub gene cluster analysis. Furthermore, we identified genes co-expressed with ACE2 in healthy lung samples and analyzed the significant genes. Additionally, to identify several candidate drugs for the treatment of COVID-19, we queried Cmap using DEGs and genes co-expressed with ACE2. Results and Conclusion: The up-regulated genes in the BALF cells of patients with COVID-19 are related to viral mRNA translation. The down-regulated genes are related to immune response functions. Genes positively correlated with ACE2 are related to immune defense and those negatively correlated are enriched in synaptic transmission functions. The results reflected prosperous viral proliferation and immune dysfunction in patients. Furthermore, ACE2 may not only mediate viral entrance, but also play an important role in immune defense. By using Cmap with transcriptome profiles of patients with COVID-19, we identified candidate drugs for the treatment of COVID-19, such as amantadine and acyclovir.

Identification of 37 Heterogeneous Drug Candidates for Treatment of COVID-19 via a Rational Transcriptomics-Based Drug Repurposing Approach

“…In comparison with other studies which employed similar computational approach for drug repurposing based on transcriptome reversal [ 27 , 28 , 29 , 31 ], we observed only a minor or no overlap of the drug candidate lists. Shared candidates were ADRA1B antagonists (nortriptyline in our study), as well as ACE inhibitor perindopril and NR1I2 agonists (econazole and ritonavir in our study) that were also identified by El-Hachem et al [ 30 ].…”

“…Several in silico drug repurposing studies based on a transcriptome reversal approach have already been published in the context of COVID-19 [ 27 , 28 , 29 , 30 , 31 ]. However, one common issue in such studies is a complete lack or insufficiency of the criteria for inclusion of datasets in the analysis which may then produce misleading results.…”

All-cause mortality among patients treated with repurposed antivirals and antibiotics for COVID-19 in Mexico City: A real-world observational study

“…amantadine, rimantadine) are thought to disrupt lysosomal trafficking, thereby impeding the release of SARS-CoV-2 ribonucleic acid (RNA) into the cell (Araújo et al, 2020[ 2 ]), and by inhibiting conductance of the envelope (E) protein (Aranda Abreu et al, 2020[ 1 ]). Acyclovir, a nucleotide analog antiviral, was found as a candidate drug for COVID-19 by potentially counteracting gene expression changes observed after SARS-CoV-2 infection (Li and Yang, 2020[ 16 ]).…”

Potential for the Repurposing of Adamantane Antivirals for COVID-19

“…In a bid to identify underlying mechanisms and candidate drugs for COVID-19, an analysis of differentially expressed genes that co-express with ACE2 indicated by the expression of RNAs isolated from bronchoalveolar lavage fluid cells of patients with COVID-19 by functional enrichment and hub gene cluster analyses were undertaken [ 11 ]. Using the connectivity map database with transcriptome profiles of patients with COVID-19, candidate drugs were identified, one of which was amantadine.…”