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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