Table 1 Possible targets to alleviate the life-threatening complications of COVID-19

Pre-Phase 1

- Vaccine (e.g., against the SARS-CoV-2 S protein) 1

(for the various technologies employed see also text and [149,150,151,152])

Phase 1 of the disease: Life cycle of the virus (extracellular – early steps of infection)

- SARS-CoV-2 neutralizing monoclonal antibodies 1

(see text and [153,154,155]; because antibody-dependent enhancement of disease [156] cannot be reliably predicted after either vaccination or treatment with antibodies, the on-going clinical trials for COVID-19 immune interventions should depend on careful analyses for safety in humans; also, preferentially the development of neutralizing antibodies after vaccination should be monitored) – (neutralizing antibodies from Eli Lilly and Regeneron Pharmaceuticals Inc. have received FDA emergency use authorization and GlaxoSmithKline/Vir Biotechnology has moved an anti-SARS-CoV-2 mAb into Phase 3 clinical trials)

- Soluble ACE2 (decoy for virus) 2

(a recent development is this field is the production of engineered human ACE2 with optimum binding to the S protein of SARS-CoV-2 [157])

- Antibodies or small molecules that target ACE2 2

- Treatments that suppress ACE2 and/or TMPRSS2 genes expression 2

- TMRPSS2 protease inhibitors 3

- Inhibitors of membrane fusion and/or clathrin-mediated endocytosis 4

Phase 1 of the disease: Life cycle of the virus (intracellular)

- Tubulin polymerization inhibitors 4,4*,7

- Inhibitors of the endosomal/lysosomal compartments 4,4*

(recent studies in non-human primates do not support the use of hydroxychloroquine -either alone or in combination with azithromycin- for the treatment of COVID-19 in humans [158]; also, chloroquine was not found to inhibit infection of human lung cells with SARS-CoV-2 [159])

- CTSB/L specific inhibitors 4

- Small molecule inhibitors of cellular pathways reshaped by SARS-CoV-2 infection

(not shown)

- Inhibitors of the virus’ main protease 5,6

- Virus’ RNA-dependent RNA polymerase inhibitors 5,6

- MHC class II/MHC class I antigen presentation enhancement 8

Phase 2 of the disease: adverse effects of COVID-19

- ACE inhibitors, AT1R blockers 10–12

- The ANG(1–7) peptide (or non-peptide analogs) 10–12

- Antioxidants or radical scavengers 10–12

- Adjunct immunotherapies (or corticosteroids) to mitigate “cytokine storm” (e.g., inhibition of IL-6 signaling) 10–12

(notably, the use of hydrocortisone [160] or dexamethasone [161] showed some beneficial effects on mortality, organ support, days alive and free of mechanical ventilation in patients with severe COVID-19)

- Anticoagulant medications to alleviate intravascular coagulation

(not shown)

- Additional life-supporting measures (e.g., ventilation or intubation)

(not shown)