FDA approved drugs with pharmacotherapeutic potential for SARS-CoV-2 (COVID-19) therapy

Abstract

In December 2019, a novel SARS-CoV-2 coronavirus emerged, causing an outbreak of life-threatening pneumonia in the Hubei province, China, and has now spread worldwide, causing a pandemic. The urgent need to control the disease, combined with the lack of specific and effective treatment modalities, call for the use of FDA-approved agents that have shown efficacy against similar pathogens. Chloroquine, remdesivir, lopinavir/ritonavir or ribavirin have all been successful in inhibiting SARS-CoV-2 in vitro. The initial results of a number of clinical trials involving various protocols of administration of chloroquine or hydroxychloroquine mostly point towards their beneficial effect. However, they may not be effective in cases with persistently high viremia, while results on ivermectin (another antiparasitic agent) are not yet available. Interestingly, azithromycin, a macrolide antibiotic in combination with hydroxychloroquine, might yield clinical benefit as an adjunctive. The results of clinical trials point to the potential clinical efficacy of antivirals, especially remdesivir (GS-5734), lopinavir/ritonavir, and favipiravir. Other therapeutic options that are being explored involve meplazumab, tocilizumab, and interferon type 1. We discuss a number of other drugs that are currently in clinical trials, whose results are not yet available, and in various instances we enrich such efficacy analysis by invoking historic data on the treatment of SARS, MERS, influenza, or in vitro studies. Meanwhile, scientists worldwide are seeking to discover novel drugs that take advantage of the molecular structure of the virus, its intracellular life cycle that probably elucidates unfolded-protein response, as well as its mechanism of surface binding and cell invasion, like angiotensin converting enzymes-, HR1, and metalloproteinase inhibitors.

Keywords: Chloroquine; Coronavirus; Lopinavir; Remdesivir; Ribavirin; Ritonavir; SARS-CoV-2.

Fig. 1

Graphical representation of HCQ action. It is believed that most important pathways involve lysosomal enzyme stabilization, antigen presentation suppression, T-cell stimulation inhibition, or cytokine cascade blockade. HCQ inhibits the proliferation of T-cells and monocytes, and decreases the production of pro-inflammatory cytokines (Il-6, Il-17, IFN-α, IFN-λ, TNF-α). Additionally, it inhibits antibody and prostaglandin (PG) production. It decreases thrombocyte aggregation, lipid levels, insulin secretion, as well as oxidative stress (Nowell and Quaranta, 1985). Another mechanism that contributes to its antimalarial properties involves the inhibition of toll-like-receptors, namely TLR-3, TLR-7, and TLR-9, in response to microbial antigens that under normal conditions induce inflammatory response. Furthermore, antimalarial drugs inhibit PG production and lipid peroxidation. Decreasing PG production involves the inhibition of phospholipase A2 activity.

Fig. 2

Summary of clinical trials on COVID-19 treatment. The chart summarizes the clinical trials to date (16^th of April 2020), which verify the effectiveness of different potential anti−COVID therapeutic agents, with regard to the therapeutic agent and the number of participating patients.

Fig. 3

Molecular targets of therapeutic agents disrupting viral invasion. ACE2 (angiotensin converting enzyme 2) - the virus fuses with host cells and multiplies by binding to the ACE2 membrane receptor, with the aid of the receptor binding domain encoded in the SARS-fusion protein S (Spike) 2-CoV (Ou et al., 2020); TMPRSS2 – the protease activates the process of cell fusion when protein S binds to ACE2; it induces receptor-dependent syncytium formation [143]; CD147 – potential alternative mediator of invasion of host cells (its role is not well established) (Wang et al., 2020c).