Repurposing Drugs for the Treatment of COVID-19 and Its Cardiovascular Manifestations

Abstract

COVID-19 is an infectious disease caused by SARS-CoV-2 leading to the ongoing global pandemic. Infected patients developed a range of respiratory symptoms, including respiratory failure, as well as other extrapulmonary complications. Multiple comorbidities, including hypertension, diabetes, cardiovascular diseases, and chronic kidney diseases, are associated with the severity and increased mortality of COVID-19. SARS-CoV-2 infection also causes a range of cardiovascular complications, including myocarditis, myocardial injury, heart failure, arrhythmias, acute coronary syndrome, and venous thromboembolism. Although a variety of methods have been developed and many clinical trials have been launched for drug repositioning for COVID-19, treatments that consider cardiovascular manifestations and cardiovascular disease comorbidities specifically are limited. In this review, we summarize recent advances in drug repositioning for COVID-19, including experimental drug repositioning, high-throughput drug screening, omics data-based, and network medicine-based computational drug repositioning, with particular attention on those drug treatments that consider cardiovascular manifestations of COVID-19. We discuss prospective opportunities and potential methods for repurposing drugs to treat cardiovascular complications of COVID-19.

Keywords: COVID-19; cardiovascular disease; drug repositioning; heart failure; myocarditis; thromboembolism.

Figure 1.

The mutual interaction and injury between COVID-19 and the cardiovascular system. Cardiovascular comorbidities are significantly correlated with the severity and mortality of COVID-19; likewise, COVID-19 can cause cardiovascular injury and a series of cardiovascular complications. Illustration Credit: Sceyence Studios.

Figure 2.

The COVID-19 disease module. SARS-CoV-2 targets are not randomly scattered over the human interactome, but form a densely connected module (covidome). The majority of the SARS-CoV-2 targets are expressed in cardiovascular tissues, potentially serving as a basis for SARS-CoV-2 infection-induced cardiovascular manifestations.

Figure 3.

A potential scheme for repositioning drug candidates to target cardiovascular manifestations of COVID-19. Differentially expressed genes can be obtained from SARS-CoV-2-induced omics data. Overlapping analysis between cardiovascular disease-associated genes and SARS-CoV-2 differentially expressed genes leads to disease gene signatures. Inverse signature correction between disease gene signatures and drug gene expression signatures from the Connectivity Map (CMap) and Library of Integrated Network-Based Cellular Signatures (LINCS) can identify potential drug candidates for targeting cardiovascular manifestation for COVID-19. The drug candidates are then subject to in vitro and in vivo validation through animal models and clinical trials in patients with COVID-19. Illustration Credit: Sceyence Studios.

Figure 4.

A network proximity approach for repositioning drugs to treat cardiovascular manifestations of COVID-19. A, COVID-19 disease module and cardiovascular disease module in the human interactome. B, For each target of a drug, a disease protein in the module closest to the target is identified and shortest path length is calculated. The average shortest path length from the targets of a drug to a disease module defines the network proximity d from the drug to the disease module. The significance is evaluated by the null distribution generated through a defined number of random modules. Illustration Credit: Sceyence Studios.