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The rapid global spread of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has created an urgent need for effective treatments to contain the current 2019 coronavirus disease pandemic (COVID-19). The availability of a global proteomics dataset has paved the way for a better understanding of the mechanism by which the virus infects host cells, which in turn involves various protein interactions.
The identification of directly interacting proteins (DIP) and differentially expressed proteins (DEP), as well as advances in interactome analysis and transcriptomics, have allowed the identification of new target molecules.
The results of these studies also contribute to drug reorientation strategies, where approved drugs could be used to target identified proteins or disrupt their pathways so that they can inhibit viral infection. The effective drug could be used for the treatment of COVID-19 disease. Systematic analysis of these data sets could lead to a more effective therapeutic intervention.
A new study has been published in Scientists progress which exploits proteomic datasets to develop an agnostic network for SARS-CoV-2-induced pathways, thus unveiling new targets and potential reorientation strategies.
Drug reorientation strategies using computational biology and machine learning
The researchers used several computational approaches, such as tailor-made methods for data integration, computer simulation, network analysis and machine learning to determine new pathways induced by SARS-CoV-2. These pathways could be targeted to develop a treatment by reusing existing and approved drugs.
Network analysis has been applied for the evaluation of genetic data sets to determine unique markers for a specific disease. Artificial neural networks have also been used to systematically study the mechanism of action (MoA) of drugs.
The team also used the agnostic construction of a network of SARS-CoV-2 (SIP) -induced proteins and the new algorithms applied to identify new targets and conducted a network-based proximity measurement analysis in -silico on key proteins of the SIP network at 6 and 24 hours after infection.
Identification of new drugs for the treatment of COVID-19
The study authors successfully identified 200 approved drugs, along with their MoA, that could potentially be used for COVID-19 treatment. Currently, 20% of these drugs are in clinical trials. In the context of MoA drugs undergoing COVID-19 clinical trials, 30 of the drugs are based on inhibiting viral replication, while only 10 are based on activating the immune response.
The authors also conducted an in-depth analysis that included characterizing all 200 drugs and their target proteins and mapping them into nine groups of pathways.
Two drugs have been identified, namely sulfasalazine and proguanil, which may reduce the rate of viral replication of SARS-CoV-2 in cellular tests. Therefore, researchers believe that these drugs could be used effectively to treat SARS-CoV-2 infection.
MoA of identified drugs
The analytical method of the present study revealed which biological pathways change significantly during infection, with large increases in proteins involved in virus replication within 24 hours. Nitric oxide (NO) is essential for viral synthesis.
During viral infection, SARS-CoV-2 Orf8 binds to γ-glutamyl hydrolase (GGH) and controls the production of NO. In addition, the helper pathway may also indirectly aid in NO synthesis while mediating the synthesis of NADP.
Sulfasalazine and proguanil invade both of these pathways and inhibit the production of NO. Sulfasalazine targets NF-κB inhibitors (NFKBIA and IKBKB) and CYP450 enzymes, while proguanil targets DHFR and CYP450 enzymes and also interacts with their associated proteins.
Currently, sulfasalazine is used as an anti-inflammatory against autoimmune diseases. As this drug has shown dual action – i.e. antiviral and anti-inflammatory action – it further increased the possibility of being used for the treatment of COVID-19. Proguanil, in combination with atovaquone, is used to treat malaria. Sulfasalazine and proguanil are known to be well tolerated drugs and have excellent safety profiles.
What is the signification ?
This study holistically mapped the protein interactions that are dramatically affected during SARS-CoV-2 infection by uncovering the hidden layer between PID and DEP. The prequalified drugs were subjected to network analysis to predict the MoA of the drugs. Drugs that could inhibit viral replication have been tested in monkey VeroE6 cells and human Calu-3 cells to further verify their effectiveness.
This research found 160 approved potential drugs that are not currently in clinical trials but may be effective for treating COVID-19. The researchers are optimistic that their data-driven computational approach could be useful in rapidly tackling the continuously emerging SARS-CoV-2 variants. This strategy could also be used to fight against future pandemics or other non-infectious diseases.
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