In silico Analyses of Immune System Protein Interactome Network, Single-Cell RNA Sequencing of Human Tissues, and Artificial Neural Networks Reveal Potential Therapeutic Targets for Drug Repurposing Against COVID-19

Abstract

Background: There is pressing urgency to identify therapeutic targets and drugs that allow treating COVID-19 patients effectively.Methods: We performed in silico analyses of immune system protein interactome network, single-cell RNA sequencing of human tissues, and artificial neural networks to reveal potential therapeutic targets for drug repurposing against COVID-19.Results: We screened 1,584 high-confidence immune system proteins in ACE2 and TMPRSS2 co-expressing cells, finding 25 potential therapeutic targets significantly overexpressed in nasal goblet secretory cells, lung type II pneumocytes, and ileal absorptive enterocytes of patients with several immunopathologies. Then, we performed fully connected deep neural networks to find the best multitask classification model to predict the activity of 10,672 drugs, obtaining several approved drugs, compounds under investigation, and experimental compounds with the highest area under the receiver operating characteristics.Conclusion: After being effectively analyzed in clinical trials, these drugs can be considered for treatment of severe COVID-19 patients. Scripts can be downloaded at https://github.com/muntisa/immuno-drug-repurposing-COVID-19.

Differential Co-Expression Network Analysis Reveals Key Hub-High Traffic Genes as Potential Therapeutic Targets for COVID-19 Pandemic

“…Previous COVID-19 studies reported that hub-high traffic genes in the brown module, such as RBX1 ( 207 – 210 ), PSMA3 ( 211 ), PSMA6 ( 212 ), PTEN ( 213 ), VPS29 ( 214 , 215 ), SNRPE ( 216 ), PSMA4 ( 217 ), TXN ( 218 ), PTGES3 ( 219 , 220 ), RHOA ( 57 , 221 , 222 ), CANX ( 209 ), B2M ( 223 ), GDI2 ( 57 , 224 , 225 ), TXNL1 ( 226 ), SUMO1 ( 147 , 227 , 228 ), PSMC2 ( 229 ), REEP5 ( 230 ), DECR1 ( 108 ), RAB10 ( 224 ), PRDX3 ( 231 , 232 ), ACTR2 ( 215 ), TNFSF13B ( 192 , 233 , 234 ), and ARPC3 ( 215 ), have a central role in host-SARS-COV-2 interactions. For example, ARDS and ALI in patients with severe COVID-19 were directly associated with increased expression of the PTEN and RHOA hub-high traffic genes, respectively ( 213 , 222 ).…”

Identification of key proteins in the signaling crossroads between wound healing and cancer hallmark phenotypes

“…In order to identify the most essential protein interactions, a WH protein–protein interactome (WH-PPi) network was created by using the human proteome of the Cytoscape StringApp, taking into account zero node addition and the highest confidence interactions (cutoff = 0.9) related to experiments, databases, and co-expression 28 , 29 . The degree of centrality represents the number of edges the nodes have in a network 30 – 32 , and this centrality index was calculated using the CytoNCA app 33 . Nodes and edges were organized through the organic layout, and the WH-PPi network was visualized through the Cytoscape software v.3.7.1 34 .…”

Problems of Pathogenesis and Pathogenetic Therapy of COVID-19 from the Perspective of the General Theory of Pathological Systems (General Pathological Processes)

“…In this situation, multi-target therapy could be used to provide a synergistic antiviral, immunomodulatory, and anti-inflammatory impact at the same time. Around 4000 clinical trials on COVID-19 have been conducted worldwide [ 297 ], employing small molecules as single or combination treatments with various antiviral medicines.…”

“…Furthermore, the computational docking results revealed that several known and newly synthesized chemical compounds had high inhibitory binding affinities with the docked SARS-CoV-2 proteins, suggesting that they could be useful lead compounds for the design and synthesis of new anti-COVID-19 agents [ 304 , 309 , 310 ]. A combination of in silico analysis of immune system protein interactome networks, single-cell RNA sequencing of human tissues, and artificial neural networks was undertaken in one of the recent (2021) studies to reveal potential therapeutic targets for drug repurposing against COVID-19 [ 297 ]. As a consequence, 47 approved drugs, 25 under-investigation compounds, and 50 experimental compounds with a strong affinity for 15 possible therapeutic targets were discovered and recommended for further research [ 297 ].…”

“…A combination of in silico analysis of immune system protein interactome networks, single-cell RNA sequencing of human tissues, and artificial neural networks was undertaken in one of the recent (2021) studies to reveal potential therapeutic targets for drug repurposing against COVID-19 [ 297 ]. As a consequence, 47 approved drugs, 25 under-investigation compounds, and 50 experimental compounds with a strong affinity for 15 possible therapeutic targets were discovered and recommended for further research [ 297 ].…”