Recent advances in management of COVID-19: A review

Abstract

The coronavirus disease 2019 (COVID-19) pandemic caused and is still causing significant mortality and economic consequences all over the globe. As of today, there are three U.S Food and Drug administration (FDA) approved vaccines, Pfizer-BioNTech, Moderna and Janssen COVID-19 vaccine. Also, the antiviral drug remdesivir and two combinations of monoclonal antibodies are authorized for Emergency use (EUA) in certain patients. Furthermore, baricitinib was approved in Japan (April 23, 2021). Despite available vaccines and EUA, pharmacological therapy for the prevention and treatment of COVID-19 is still highly required. There are several ongoing clinical trials investigating the efficacy of clinically available drugs in treating COVID-19. In this study, selected novel pharmacological agents for the possible treatment of COVID-19 will be discussed. Point of discussion will cover mechanism of action, supporting evidence for safety and efficacy and reached stage in development. Drugs were classified into three classes according to the phase of viral life cycle they target. Phase I, the early infective phase, relies on supportive care and symptomatic treatment as needed. In phase II, the pulmonary phase, treatment aims at inhibiting viral entry or replication. Drugs used during this phase are famotidine, monoclonal antibodies, nanobodies, ivermectin, remdesivir, camostat mesylate and other antiviral agents. Finally, phase III, the hyper-inflammatory phase, tocilizumab, dexamethasone, selective serotonin reuptake inhibitors (SSRI), and melatonin are used. The aim of this study is to summarize current findings and suggest gaps in knowledge that can influence future COVID-19 treatment study design.

Keywords: COVID-19; Dexamethasone; Famotidine; Fluoxetine; Fluvoxamine; Ivermectin; Melatonin; Monoclonal antibodies; Nanobodies; Remdesivir; SARS-CoV-2; SSRI; Serotonin; Tocilizumab.

Graphical abstract

Fig. 1

Mechanisms of COVID-19 entry into the host cell. COVID-19 can invade the host cell by two mechanism: direct fusion or through the endocytic pathway.

Fig. 2

The structure of nanobodies (Nbs) and different multivalent nanobodies. Camelid species unlike conventional antibodies (IgG) only consist of two light chains. The variable domain highlighted is known as the VHH domain or more commonly nanobody. Nbs can be bioengineered as monovalent or multivalent. Multivalent Nbs can be further classified into bivalent (two identical Nbs), biparatropic (two different Nbs) or trivalent (three identical Nbs).

Fig. 3

Nanobodies inhibit the viral entry into the host cell. Nanobodies bind to viral spike proteins inhibiting spike-ACE2 binding.

Fig. 4

Viral inhibition by Lysosomotropic agent. Lysosomotropism agents increase the endosomal/lysosomal pH (represented in green) which prevents viral vacuole escape into the cytosol.

Fig. 5

Ph-dependant viral release into the cytosol. The pH decreases gradually as the endosome gets closer to the nucleus (indicated by a more intense yellow color). The virus uses the increasing acidic environment as a signal to exit the endosome.

Fig. 6

Functional inhibitors of Acid sphingomyelinase (FIASMA) by fluoxetine. ASM is a membrane bound enzyme. Fluoxetine displaces ASM which turns it into inactive. Displacement from the membrane also subjects it to proteolysis by proteolytic enzymes.