A novel logical model of COVID-19 intracellular infection to support therapies development.

In this paper, a logical-based mathematical model of the cellular pathways involved in the COVID-19 infection has been developed to study various drug treatments (single or in combination), in different illness scenarios, providing insights into their mechanisms of action. Drug simulations suggest that the effects of single drugs are limited, or depending on the scenario counterproductive, whereas better results appear combining different treatments. Specifically, the combination of the anti-inflammatory Baricitinib and the anti-viral Remdesivir showed significant benefits while a stronger efficacy emerged from the triple combination of Baricitinib, Remdesivir, and the corticosteroid Dexamethasone. Together with a sensitivity analysis, we performed an analysis of the mechanisms of the drugs to reveal their impact on molecular pathways. Author summary: The paper introduces a logical-based mathematical model of the cellular pathways involved in the COVID-19 infection. The aim of the model is to study, in a qualitative but comprehensive way, the cellular mechanisms developed during the virus infection with the principal focus on drug treatments. The model is able to reproduce various illness scenarios: from the early infection stages to the late illness stages characterized by strong immune reaction usually evolving in the so-called cytokine storm. Different drug effects have been tested singularly and in combination treatments. Computational sensitivity analysis was performed on the model along with the analysis of the mechanisms of the drugs to reveal their impact on molecular pathways. The results show that the effect of single drugs may be limited or counterproductive, depending on the illness stage. The highest predicted efficacy is obtained by combining three different treatments: the anti-inflammatory Baricitinib, the anti-viral Remdesivir and the corticosteroid Dexamethasone. This triple combination therapy has been analyzed not only in terms of global cellular effect but also in function of the involved internal pathways, suggesting the rational mechanisms for its successfulness. [ABSTRACT FROM AUTHOR]