Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review
Abstract
:1. Introduction
2. Materials and Methods
3. Results
3.1. Targeted Enzyme Inhibitors
3.1.1. RNA-Dependent RNA Polymerase Inhibitors
Remdesivir
Favipiravir
3.1.2. Neuraminidase Inhibitors
3.1.3. Protease Inhibitors
TMPRSS2 Inhibitors
Disulfiram
Angiotensin-Converting Enzyme 2 Inhibitors
3.1.4. Kinase Inhibitors
Imatinib
Baricitinib
3.1.5. Ribavirin
3.2. Immunomodulators
3.2.1. Convalescent Plasma
3.2.2. Humanized Antibodies
Spike Protein Antibodies
IL-6 Receptor Antibodies
3.2.3. Interferons
3.2.4. Cyclosporine A
3.2.5. Mycophenolic Acid
3.2.6. Corticosteroids
3.3. Antibiotics
3.3.1. Glycopeptide Antibiotics
3.3.2. Nitazoxanide
3.4. Other Medications
3.4.1. Umifenovir
3.4.2. Indomethacin
3.4.3. Hydroxychloroquine/Chloroquine
3.4.4. Chlorpromazine
3.4.5. Toremifene Citrate
3.4.6. Loperamide
4. Discussion
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
AAK-1 | Adaptor-associated kinase |
Abl2 | Abelson tyrosine-protein kinase 2 |
ACE | Angiotensin-converting enzyme |
ACE2 | Angiotensin-converting enzyme 2 |
ACTT-1 | Adaptive COVID-19 Treatment Trial |
COVID-19 | Coronavirus disease 2019 |
COX | Cyclooxygenase |
HIV | Human immunodeficiency virus |
ICU | Intensive care unit |
IL-6 | Interleukin 6 |
JAK | Janus kinase |
LPV/r | Lopinavir/ritonavir |
MERS-CoV | Middle East respiratory syndrome coronavirus |
MPA | Mycophenolic acid |
NAAE | N-(2-aminoethyl)-1-aziridineethanamine |
NSAID | Non-steroidal anti-inflammatory drug |
NTZ | Nitazoxanide |
ORCHID | Outcomes Related to COVID-19 treated with hydroxychloroquine among Inpatients with symptomatic Disease |
PLpro | Papain-like protease |
RdRp | RNA-dependent RNA polymerase |
RDV-TP | Remdesivir triphosphate |
RECOVERY | Randomised Evaluation of COVID-19 therapy |
RSV | Respiratory Syncytial Virus |
S protein | Spike protein |
SARS-CoV | Severe acute respiratory syndrome coronavirus |
SARS-CoV-2 | Severe acute respiratory syndrome coronavirus 2 |
TMPRSS2 | Transmembrane protease, serine 2 |
USFDA | U.S. Food and Drug Administration |
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Class | Medication | Mechanism of Action | Evidence in SARS | Evidence in MERS | Evidence in COVID-19 | Trials (n) | |||
---|---|---|---|---|---|---|---|---|---|
In Vitro | In Vivo | In Vitro | In Vivo | In Vitro | In Vivo | ||||
Enzyme Inhibitors | Remdesivir | RNA dependent RNA polymerase inhibitor | [4,10] | [4,10] | [4,10] | [4,11] | [4,9,12] | [13,14] | 13 |
Favipiravir | RNA dependent RNA polymerase inhibitor | [12,15] | [17] | 19 | |||||
Oseltamivir | Interferes with release of viral progeny from infected host cells | [20] | 3 | ||||||
Lopinavir/Ritonavir | Inhibits viral protease enzyme. Ritonavir also inhibits metabolism of lopinavir | [24,25] | [24] | [27] | [28,29] | 27 | |||
Camostat | Inhibits TMPRSS2 enzyme | [30,31] | [30,31] | 2 | |||||
Nafamostat | Inhibits TMPRSS2 enzyme | [32] | [33] | 3 | |||||
Bromhexine | Inhibits TMPRSS2 enzyme | 2 | |||||||
Disulfiram | Inhibits hepatic aldehyde dehydrogenase; inhibits PLpro | [35] | [35] | 0 | |||||
N-(2-Aminoethyl)-1-aziridineethanamine | ACE2 Inhibitor (preclinical) | [40] | 0 | ||||||
Imatinib | Inhibits tyrosine kinase | [43,44] | [43,44] | 3 | |||||
Baricitinib | Inhibits JAK1 and AAK1 kinases, interferes with viral endocytosis, blunts cytokine storm | [47] | 4 | ||||||
Ribavirin | Inhibits inosine monophosphate dehydrogenase enzyme | [49] | [51] | [50] | [52] | 6 | |||
Immuno-modulators | Convalescent Plasma | Antibodies target SARS-CoV-2 | [55] | [56,57,58] | 111 | ||||
mAb 4C2h | Neutralizes spike receptor binding domain of MERS-CoV (preclinical) | [60] | 0 | ||||||
mAb 5H10 | Neutralizes spike receptor binding domain of SARS-CoV (preclinical) | [61] | 0 | ||||||
Tocilizumab | Humanized IL-6 receptor antibody | [62] | 21 | ||||||
Sarilumab | Humanized IL-6 receptor antibody | [63] | 13 | ||||||
Interferons | Activates host immune system | [65,66] | [64,66] | [66] | [66] | [66] | [52,68] | 49 | |
Cyclosporine A | Calcineurin inhibitor | [70] | [70] | [73] | 3 | ||||
Mycophenolic Acid | Immunosuppressant; may inhibit PLpro | [45] | [45] | 0 | |||||
Methylprednisolone | Suppresses host inflammatory responses | [75,76] | [75,76,77] | [76,77] | 10 | ||||
Dexamethasone | Suppresses host inflammatory responses | [75,76] | [75,76] | [76,78] | 11 | ||||
Antibiotics | Teicoplanin | Inhibits cathepsin L-mediated spike cleavage | [80] | [80] | [80,82] | 1 | |||
Dalbavancin | Unclear | [81] | [81] | 0 | |||||
Oritavancin | Unclear | [81] | [81] | 0 | |||||
Nitazoxanide | Uncouples oxidative phosphorylation | [37,84] | 14 | ||||||
Other Medications | Umifenovir | Unclear | [85] | [37,86] | 4 | ||||
Indomethacin | NSAID; inhibits COX | [87] | [88] | 1 | |||||
Hydroxychloroquine/Chloroquine | Increases endosomal pH of phagolysosome interferes with viral fusion with cell; modifies ACE2 receptor; modifies protein degradation pathways | [60] | [91] | [92,93,95] | >150 | ||||
Chlorpromazine | Dopamine receptor antagonist; inhibits clathrin-mediated viral endocytosis | [60] | [60] | [97] | 2 | ||||
Toremifene Citrate | Estrogen receptor antagonist | [43,100] | [43,100] | 0 | |||||
Loperamide | Mu opioid receptor agonist | [101] | [101] | 0 |
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Santos, J.; Brierley, S.; Gandhi, M.J.; Cohen, M.A.; Moschella, P.C.; Declan, A.B.L. Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review. Viruses 2020, 12, 705. https://doi.org/10.3390/v12070705
Santos J, Brierley S, Gandhi MJ, Cohen MA, Moschella PC, Declan ABL. Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review. Viruses. 2020; 12(7):705. https://doi.org/10.3390/v12070705
Chicago/Turabian StyleSantos, Jennifer, Stephanie Brierley, Mohit J. Gandhi, Michael A. Cohen, Phillip C. Moschella, and Arwen B. L. Declan. 2020. "Repurposing Therapeutics for Potential Treatment of SARS-CoV-2: A Review" Viruses 12, no. 7: 705. https://doi.org/10.3390/v12070705