Approaches to the Potential Therapy of COVID-19: A General Overview from the Medicinal Chemistry Perspective

Abstract

In spite of advances in vaccination, control of the COVID-19 pandemic will require the use of pharmacological treatments against SARS-CoV2. Their development needs to consider the existence of two phases in the disease, namely the viral infection and the inflammatory stages. The main targets for antiviral therapeutic intervention are: (a) viral proteins, including the spike (S) protein characteristic of the viral cover and the viral proteases in charge of processing the polyprotein arising from viral genome translation; (b) host proteins, such as those involved in the processes related to viral entry into the host cell and the release of the viral genome inside the cell, the elongation factor eEF1A and importins. The use of antivirals targeted at host proteins is less developed but it has the potential advantage of not being affected by mutations in the genome of the virus and therefore being active against all its variants. Regarding drugs that address the hyperinflammatory phase of the disease triggered by the so-called cytokine storm, the following strategies are particularly relevant: (a) drugs targeting JAK kinases; (b) sphingosine kinase 2 inhibitors; (c) antibodies against interleukin 6 or its receptor; (d) use of the traditional anti-inflammatory corticosteroids.

The effect of various compounds on the COVID mechanisms, from chemical to molecular aspects

“… Compound Chemical structure Target Software Ref. 6TG PLpro – [ 85 ] 6MP PLpro – [ 85 ] CMK PLpro – [ 84 ] Cm –FF–H PLpro – [ 84 ] VIR251 PLpro OPLS force field, CovDock, Maestro (Schrödinger LLC) [ 82 ] F403_0159 PLpro OPLS force field, CovDock, Maestro (Schrödinger LLC) [ 82 ] Curcumin PLpro OPLS force field, CovDock, Maestro (Schrödinger LLC) [ 82 ] Afatinib PLpro OPLS force field, CovDock, Maestro (Schrödinger LLC) [ 82 ] Anagliptin PLpro OPLS force field, CovDock, Maestro (Schrödinger LLC) [ 82 ] Bortuzomib PLpro – [ 84 ] Disulfiram PLpro – [ 101 ] Lopinavir PLpro – [ 102 ] …”

“…Lopinavir, initially developed as an anti-HIV drug, inhibits the Mpro because of the analogy of the drug with the transition state of the hydrolysis reaction. Lopinavir is a substrate of the CYP3A4 cytochrome, thus it is physically combined with ritonavir, which is a suicide cytochrome inhibitor that acts by the metabolic generation of an isocyanate intermediate that then carbamoylates a nucleophilic residue at the cytochrome [ 102 ]. ( Fig.…”

“…Remdesivir (RDV, GS-5734) is a pro-drug that is a 1′-Ribose cyano substitution of adenosine nucleotide analog. Its adenine fragment is modified, and The presence of a cyano group at the anomeric carbon is unusual, and it leads to a lower activity on mammal RNA polymerases [ 102 ]. Upon entering the body, Remdesivir is hydrolyzed and phosphorylated through metabolism, Remdesivir monophosphate (RDV-MP) is its active form of Remdesivir with a negatively charged and polar monophosphate moiety, actually, this monophosphate increases the active triphosphate metabolite (RDV-TP) [ 143 , 144 ].…”

Cyanobacteria and Algae-Derived Bioactive Metabolites as Antiviral Agents: Evidence, Mode of Action, and Scope for Further Expansion; A Comprehensive Review in Light of the SARS-CoV-2 Outbreak

“…Although some vaccines against COVID-19 have been produced and are being successfully used to prevent infections and/or reduce disease severity, antiviral drugs are still needed to treat symptomatic patients [ 13 ]. Nevertheless, despite the fact that a few antivirals have already proved effective, the discovery of new drugs could have several advantages, e.g., greater effectiveness, broader range of action (also toward new variants), and lower cost, as well as for a better worldwide supply (for example, to the poorest countries) [ 14 ]. Despite the numerous articles about COVID-19, limited research has been carried out considering algae-derived bioactive metabolites as potential therapeutic agents.…”

Isolation of Functional SARS-CoV-2 Antigen-Specific T-Cells with Specific Viral Cytotoxic Activity for Adoptive Therapy of COVID-19

“…Unfortunately, COVID-19 treatment is still an unmet medical need [20,21]. Passive humoral immunity can be immediately acquired by the infusion of plasma from convalescent donors [22].…”