Therapeutic options for the 2019 novel coronavirus (2019-nCoV)-Nature Review Drug Discovery
Diagnostic antibodies and antigens for Companion Animal disease testing
● Rabbit
Diagnostic antibodies and antigens for Swine disease testing
Diagnostic antibodies and antigens for Avian disease testing
Diagnostic antibodies and antigens for Multiple animal disease testing
Diagnostic antibodies and antigens for Ruminant disease testing
● Deer
Diagnostic antibodies and antigens for infectious and non-infectious Equine/Horse disease testing
SOCAIL MEDIA
Guangdi Li1 and Erik De Clercq2
1 Department of Epidemiology and Health Statistics, Xiangya School of Public Health, Central South University, Changsha, China.
2 Department of Microbiology, Immunology and Transplantation, Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
Supplementary Table 1 | Summary of antiviral compounds against human coronaviruses
| Infectious diseases | Drug targets | Antiviral agents | Reported mechanism of action | Status | Ref. |
| Virus-based treatment strategies | |||||
|
2019-nCoV; Influenza |
RdRp | Favipiravir | Inhibits RdRp |
• Approved for influenza in Japan • Randomized trial for 2019-nCoV (ChiCTR2000029544, ChiCTR2000029600) |
[1,2] |
| 2019-nCoV, MERS-CoV, SARS-CoV, RSV, HCV | RdRp | Ribavirin | Inhibits viral RNA synthesis and mRNA capping |
• Approved for HCV and RSV • Randomized trial for 2019-nCoV in combination a pegylated interferon (ChiCTR2000029387). • Randomized trial for SARS (NCT00578825) |
[2-8] |
| 2019-nCoV | RdRp | Penciclovir | Inhibits RdRp | Approved for HSV | [2] |
| 2019-nCoV, MERS-CoV, SARS-CoV | RdRp | Remdesivir (GS-5734) | Terminates the non-obligate chain |
• Phase 3 for 2019-nCoV (NCT04252664, NCT04257656) • Phase 1 for Ebola (NCT03719586) |
[1,2, 9-11] |
|
Broad-spectrum (e.g. SARS- CoV, MERS- CoV, IAV) |
RdRp | Galidesivir (BCX4430) | Inhibits viral RNA polymerase function by terminating non- obligate RNA chain |
• Phase 1 for yellow fever (NCT03891420) • Phase 1 for Marburg virus (NCT03800173) |
[12] |
| Broad-spectrum (e.g. CoV, ZIKV, CHIKV) | RdRp |
6′-Fluorinated- aristeromycin analogues (Compound 2c) |
Inhibits the activity of RdRp and host cell S-adenosyl-L- homocysteine hydrolase | Preclinical | [13] |
| HCoV-NL63, MERS-CoV | RdRp | Acyclovir fleximer analogues (Compound 2) | Doubly flexible nucleoside analogues inhibit RdRp | Preclinical | [14] |
|
MERS-CoV, SARS-CoV |
PLpro | Disulfiram | Inhibits PLpro |
Approved for chronic alcohol dependence |
[15] |
| MERS-CoV, SARS-CoV | PLpro |
Thiopurine analogues (6-mercaptopurine and 6-thioguanine) |
Inhibits PLpro | Preclinical | [16] |
| MERS-CoV | PLpro | Compound 6 | Inhibits PLpro | Preclinical | [17] |
| 2019-nCoV; MERS-CoV, SARS-CoV; HCoV-229E; HIV, HPV | 3CLpro | Lopinavir | Inhibits 3CLpro |
• Approved for HIV • Phase 3 for 2019-nCoV (NCT04252274, NCT04251871, NCT04255017, ChiCTR2000029539) • Phase 2/3 for MERS (NCT02845843) |
[11, 18-21] |
| 2019-nCoV, MERS-CoV | 3CLpro | Ritonavir | Inhibits 3CLpro |
• Approved for HIV • Phase 3 for 2019-nCoV (NCT04251871, NCT04255017, NCT04261270) • Phase 2/3 for MERS (NCT02845843) |
[11,18, 20,21] |
| 2019-nCoV | 3CLpro | Darunavir and cobicistat | Inhibits 3CLpro |
• Approved for HIV • Phase 3 for 2019-nCoV (NCT04252274) |
– |
| 2019-nCoV | 3CLpro |
ASC09F (HIV protease inhibitor) |
Inhibits 3CLpro |
Phase 3 for 2019-nCoV in combination with oseltamivir (NCT04261270) |
– |
|
MERS-CoV, SARS-CoV |
3CLpro | GC376 | Inhibits 3CLpro | Preclinical | [22] |
| MERS-CoV | 3CLpro | GC813 | Inhibits 3CLpro | Preclinical | [23] |
| SARS-CoV | 3CLpro | Phenylisoserine derivatives (SK80) | Inhibits 3CLpro | Preclinical | [24] |
| MERS-CoV, SARS-CoV | 3CLpro |
Peptidomimetic inhibitors (Compound 6) |
Inhibits 3CLpro | Preclinical | [25] |
| HCoV-229E | 3CLpro |
1,2,3-triazoles (Compound 14d) |
Inhibits 3CLpro | Preclinical | [26] |
| SARS-CoV, MERS-CoV | 3CLpro |
Neuraminidase inhibitor analogues (compound 3k) |
Inhibits 3CLpro | Preclinical | [27] |
| SARS-CoV | 3CLpro |
Unsymmetrical aromatic disulfides |
– | Preclinical | [28] |
| SARS-CoV | 3CLpro | Pyrithiobac derivatives (6-5) | Inhibits SARS-CoV 3CLpro | Preclinical | [29] |
| SARS-Cov, HCV | Helicase | Bananins and 5- hydroxychromone derivatives | Inhibits ATPase and helicase activities | Preclinical | [30] |
|
SARS-CoV, MERS-CoV, MHV |
Helicase | SSYA10-001 and ADKs | Inhibits helicase without affecting ATPase activity | Preclinical | [31,32] |
| MERS-CoV | Helicase | Triazole derivatives (Compound 16) | Inhibits ATPase and helicase activities | Preclinical | [33] |
| 2019-nCoV, MERS-CoV | Spike glycoprotein | Nafamostat | Inhibits spike-mediated membrane fusion | Approved for anticoagulant therapy in Asian countries | [2,34] |
| SARS-CoV | Spike glycoprotein | Griffithsin |
Griffithsin binds to the SARS- CoV spike glycoprotein, thus inhibiting viral entry |
Phase 1 for the prevention of HIV transmission (NCT02875119 and NCT04032717) |
[35,36] |
|
Broad-spectrum (SARS-CoV, MERS-CoV, influenza) |
Spike glycoprotein | Peptide (P9) | Inhibits spike protein-mediated cell-cell entry or fusion | Preclinical | [37] |
| MERS-CoV, IAV | Spike glycoprotein |
α-Helical lipopeptides (e.g. LLS, FFS, IIS, IIK) |
Inhibit spike protein-mediated cell-cell entry or fusion | Preclinical | [38] |
| MERS-CoV |
S2 subunit of the spike glycoprotein |
HR1P, HR1M, HR1L, HR2L, HR2P, HR2L |
Inhibits MERS-CoV replication and spike protein-mediated cell- cell fusion |
Preclinical | [39-41] |
| MERS-CoV |
S2 subunit of the spike glycoprotein |
HR2P-M1 HR2P-M2 |
Inhibits MERS-CoV spike protein-mediated cell-cell fusion and infection |
Preclinical |
[39,42, 43] |
| MERS-CoV | Spike glycoprotein | P21S10 | Inhibits spike protein-mediated cell−cell fusion | Preclinical | [44] |
| MERS-CoV |
Spike glycoprotein |
Dihydrotanshinone E-64-C, and E-64-D |
Blocks the endosomal entry pathway |
Preclinical | [45,46] |
| HCoV (e.g. MERS, SARS) | Spike glycoprotein |
OC43-HR2P (most promising EK1) |
Inhibits pan-CoV fusion | Preclinical | [47] |
| MERS-CoV | Spike glycoprotein | MERS-5HB | Inhibits pseudo typed MERS- CoV entry and S protein- mediated syncytial formation | Preclinical | [48] |
| HCoV-229E | Spike glycoprotein |
229E-HR1P 229E-HR2P |
Inhibits spike protein-mediated cell-cell fusion | Preclinical | [49] |
| MERS-CoV |
Nucleocapsid protein (possible) |
Resveratrol | – | Clinical stages for several diseases (e.g. heart disease) | [50] |
| HCoV, influenza virus | Fusion inhibitors |
1-thia-4-azaspiro [4.5] decan-3-one derivatives (Compound 8n) |
– | Preclinical | [51] |
| MERS-CoV, SARS-CoV |
DNA metabolism inhibitor |
Gemcitabine hydrochloride | – | Approved as chemotherapy | [46] |
| MERS-CoV, SARS-CoV | – | Amodiaquine | – | Approved for malaria | [46] |
|
MERS-CoV, SARS-CoV |
– | Mefloquine | – | Approved for malaria | [46] |
|
MERS-CoV, SARS-CoV HCoV-229E |
– | Loperamide | – | Approved as an antidiarrheal agent | [19] |
|
2019-nCoV; Influenza virus; |
? | Arbidol (Umifenovir) | ? |
• Approved for influenza in Russia and China • Phase 4 for 2019-nCoV (NCT04260594, NCT04254874, NCT04255017) |
– |
|
2019-nCoV; Influenza virus; |
? | Oseltamivir | Oseltamivir is an influenza neuraminidase inhibitor. |
• Approved for influenza • Phase 4 for 2019-nCoV (NCT04255017), Phase 3 for 2019- nCoV (NCT04261270) |
– |
| Host-based treatment strategies | |||||
| 2019-nCoV; SARS-CoV; MERS-CoV | Interferon response | Recombinant interferons (interferon-a, interferon-b,interferon-g | Exogenous interferons |
• Approved for metastatic renal cell carcinoma (IFN-α2a), melanoma (IFN-α2b), multiple sclerosis (IFN- β1a, 1b), chronic granulomatous disease (IFN-γ) • Randomized trial for 2019-nCoV (NCT04251871, ChiCTR2000029638) |
[3-8, 21] |
| 2019-nCoV SARS-CoV MERS-CoV | Endosomal acidification | Chloroquine |
A lysosomatropic base that appears to disrupt intracellular trafficking and viral fusion events |
• Approved for malaria and certain amoeba infections • Open-label trial for 2019-nCoV (ChiCTR2000029609) |
[2,19, 52,53] |
| Broad-spectrum (e.g. coronaviruses, 2019-nCoV) | Interferon response | Nitazoxanide |
Induces the host innate immune response to produce interferons (aand b) by the host’s fibroblasts and protein kinase R (PKR) activation |
Approved for diarrhea treatment | [2,54] |
| SARS-CoV, MERS-CoV, HIV, HCV | Cyclophilins | Cyclosporine A |
Cyclophilin inhibitor that could modulate the interaction of cyclophilins with SARS-CoV nsp1 and the calcineurin–NFAT pathway |
Approved for immunosuppression during organ transplantation | [55-58] |
| SARS-CoV, MERS-CoV, HIV, HCV | Cyclophilins | Alisporivir |
Modulates the interaction of cyclophilins with SARS-CoV nsp1 and the calcineurin–NFAT pathway |
Phase 3 for HCV (e.g. NCT01860326) |
[55- 57,59] |
| MERS-CoV SARS-CoV | Abelson kinase | Imatinib mesylate |
Blocks events of early viral entry and/or post-entry |
Approved for treating cancers | [46,60] |
|
MERS-CoV, SARS-CoV |
Abelson kinase |
Dasatinib | – | Approved for treating cancers | [46] |
| MERS-CoV SARS-CoV | Abelson kinase | Selumetinib |
Inhibits the ERK/MAPK and PI3K/AKT/mTOR signaling pathways |
Clinical trials for cancers (e.g. non- small cell lung cancer, thyroid cancer) | [61] |
| MERS-CoV, SARS-CoV | Abelson kinase | Trametinib |
Inhibits the ERK/MAPK and PI3K/AKT/mTOR signaling pathways |
Approved for treating cancers | [61] |
| MERS-CoV | Kinase signaling pathways | Rapamycin |
Inhibits the ERK/MAPK and PI3K/AKT/mTOR pathways significantly inhibited MERS- CoV replication |
Approved originally as an antifungal agent | [61] |
| MERS-CoV | Tyrosine kinases | Saracatinib | – | Approved for treating cancers | [62] |
| SARS-CoV MERS-CoV | Clathrin- mediated endocytosis |
Chlorpromazine, Triflupromazine, Fluphenazine, Thiethylperazine, Promethazine |
Antipsychotic that affects the assembly of clathrin-coated pits at the plasma membrane | The former three were approved as antipsychotic agents | [19,46] |
| Broad-spectrum (HCoV-229E) | Interferon response |
Cyclophilin inhibitors (Compound 30) |
Inhibiting the activity of PPIase | Preclinical | [63] |
|
SARS-CoV MERS-CoV HCoV-229E |
Endosomal protease | K11777, Camostat |
Blocks endosomal protease- mediated cleavage and the endosomal entry pathway |
Preclinical | [64] |
| SARS-CoV, MERS-CoV, HCoV-229E |
Host cell membrane- bound viral replication complex |
K22 | Inhibits membrane-bound RNA synthesis and double membrane vesicle formation | Preclinical | [65,66] |
|
Broad-spectrum (influenza virus, HCoV, Ebola, HIV, HCV) |
Antibiotics | Teicoplanin derivatives | – | Widely used for treating gram-positive infections in Europe | [67] |
|
Broad-spectrum (e.g. CoV, influenza virus, RSV) |
– | Benzo-heterocyclic amine derivative (N30) | Depression of IMPDH activity | Preclinical | [68] |
| MERS-CoV, HBV, HCV | – | Mycophenolic acid | Inhibits IMPDH and guanine monophosphate synthesis | Approved immunosuppressant during organ transplantation | [16,69] |
|
MERS-CoV, HCoV-229E, EBOV, Picornaviridae |
eIF4A | Silvestrol | Inhibits the DEAD-box RNA helicase eIF4A to affect virus translation | Potential anticancer rocaglate derivative | [70] |
|
Broad-spectrum (influenza A and B, RSV, HCoV) |
DHODH | Pyrimidine (FA-613) | Inhibits DHODH | Preclinical | [71] |
|
SARS-CoV, MERS-CoV, influenza |
– | Convalescent plasma | Inhibits virus entry to the target cells | Phase 2 (NCT02190799 withdrawn) | [72-74] |
Abbreviations
3CLpro: 3C-like protease, CHIKV: Chikungunya virus, DHODH: dihydroorotate dehydrogenase, HBV: hepatitis B virus, HCoV: human coronavirus, HCV: hepatitis C virus, IAV: influenza A virus, IMPDH: inosine-monophosphate dehydrogenase, IMPTH: inosine-5’-monophosphate dehydrogenase, JEV: Japanese encephalitis virus, MERS: Middle East respiratory syndrome, MERSCoV: Middle East respiratory syndrome coronavirus, PEDV: porcine epidemic diarrhea virus, PLpro: papain-like protease, PPIase: peptidyl-prolyl isomerase, RBD: receptor-binding domain, RdRp: RNA-dependent RNA polymerase, RSV: respiratory syncytial virus, SARS-CoV: severe acute respiratory syndrome coronavirus, ZIKV: Zika virus.
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