On 30 January 2020, the World Health Organization (WHO) declared the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic a public health emergency of international concern. The viral outbreak led in turn to an exponential growth of coronavirus disease 2019 (COVID-19) cases, that is, a multiorgan disease that has led to more than 6.3 million deaths worldwide, as of June 2022. There are currently few effective drugs approved for treatment of SARS-CoV-2/COVID-19 patients. Many of the compounds tested so far have been selected through a drug repurposing approach, that is, by identifying novel indications for drugs already approved for other conditions. We here present an up-to-date review of the main Food and Drug Administration (FDA)–approved drugs repurposed against SARS-CoV-2 infection, discussing their mechanism of action and their most important preclinical and clinical results. Reviewed compounds were chosen to privilege those that have been approved for use in SARS-CoV-2 patients or that have completed phase III clinical trials. Moreover, we also summarize the evidence on some novel and promising repurposed drugs in the pipeline. Finally, we discuss the current stage and possible steps toward the development of broadly effective drug combinations to suppress the onset or progression of COVID-19.

One of the deadliest pandemics of the 21st century is being driven by SARS-CoV-2, a significant betacoronavirus, causing severe to moderate respiratory tract infections and represents a major public health threat than other human coronaviruses like severe acute respiratory syndrome (SARS) CoV and Middle East respiratory syndrome (MERS), which has been ravaging the world’s health, social life, and the economy. In response to the sixth wave of SARS-CoV-2, we aim to develop novel innovative viral replication inhibitor therapeutics. We achieved highly specific siRNAs by optimizing RNAi efficacy and reducing potential side effects and considering various factors such as target RNA variations, thermodynamics, accessibility of the siRNA, and off-target effects. Out of 258 siRNAs targeting conserved regions, four siRNAs (siRNA1, siRNA2, siRNA3, siRNA4) were chosen based on their predicted potency and high specificity that target critical highly conserved areas (NSP8, NSP12, and NSP14) in the viral genomes of SARS, MERS, and SARS-CoV2 with no predicted human genome off-targets. We assess the effectiveness of the four siRNAs on SARS-CoV2 strain hCoV-19/Egypt/NRC-03/2020. In VeroE6 cells, the selected siRNAs at a concentration 100nM had no cellular toxicity. siRNA2 significantly reduced viral replication with a knockdown percentage of 98% after 24 hr post-infection. In addition, siRNA4 had a statistical significance and knockdown percentage, in S gene and ORF1b gene, of 94% in viral replication. SiRNA2 and siRNA4 could be considered as potential siRNA therapy for SARS-CoV-2 infection.