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.

Keywords: 3CLpro inhibitors; IL6 antibodies; JAK-STAT inhibitors; RdRp inhibitors; S antibodies; SARS-CoV-2; SphK2 inhibitors; corticoids; serine protease inhibitors.

Figure 1

The drug repositioning process.

Figure 2

Stages in the evolution of the COVID-19 infection.

Figure 3

Schematic structure of the SARS-CoV2 virus and its prefusion spike protein (pdb 6VXX).

Figure 4

A schematic summary of the cell multiplication cycle of the SARS-CoV2 virus. The main sites for the action of drugs discussed in this review are shown in bold.

Figure 5

The initial stages of the entry process of SARS-CoV2 virus to the host cell and some points of drug action.

Figure 6

Two pathways explaining the potential beneficial effects of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers in COVID-19 patients.

Figure 7

Structure of losartan, an angiotensin receptor blocker.

Figure 8

Some inhibitors of the human TMPRSS2 enzyme.

Figure 9

The viral genome release process and some of its inhibitors.

Figure 10

(A) Structures of chloroquine and hydroxychloroquine. (B) Protonation equilibria in the chloroquine molecule. (C) Retention of chloroquine in acidic vesicles.

Figure 11

Interaction of umifenovir with cell membrane phospholipids.

Figure 12

Inhibition of the viral 3CL protease by lopinavir.

Figure 13

Ritonavir as a pharmacokinetic enhancer of lopinavir.

Figure 14

Structures of lufotrelvir, PF-00835231 and nirmatrelvir.

Figure 15

Interaction of the SARS-CoV2 3CL protease with: (A) PF-00835231 (pdb 6XHM). (B) Nirmatrelvir (pdb 7VH8).

Figure 16

Processes involved in SARS-CoV2 RNA replication. The structure of the RdRp enzyme was generated from pdb 6M71.

Figure 17

General mechanism of action of nucleoside-type RNA polymerase inhibitors.

Figure 18

Compared structures of ATP and remdesivir.

Figure 19

Bioactivation of remdesivir.

Figure 20

Bioactivation and mechanism of action of bemnifosbuvir.

Figure 21

Bioactivation and mechanism of action of favipiravir.

Figure 22

Structures of additional RNA polymerase inhibitors assayed against COVID-19.

Figure 23

Bioactivation and mechanism of action of molnupiravir.

Figure 24

(A) Natural source and structure of plitidepsin. (B) Antiviral mechanism of action of plitidepsin.

Figure 25

Structure of ivermectin.

Figure 26

Structures of JAK1/JAK2 kinase inhibitors used against COVID-19.

Figure 27

The role of the JAK-STAT pathway in COVID-related hyperinflammation.

Figure 28

Mechanism of action of opaganib.

Figure 29

Some corticoids employed in COVID-19 patients.

Figure 30

Structure of aviptadil.

Figure 31

Antibodies targeting: (A) Interleukin 6 receptor. (B) Interleukin 6.