Table 3. Representative host-based treatment strategies for CoV infections.
| Targeted host factors | Examples | Mechanism of action | Status | Comments | Refs |
|---|---|---|---|---|---|
| Broad-spectrum host innate immune response | |||||
| Interferon response | Recombinant interferons (interferon alfa, interferon beta, interferon gamma) | Exogenous interferons | Marketed |
• Broad spectrum against many CoVs and other viruses • Recombinant interferon beta was more potent than interferon alfa for SARS-CoV and MERS-CoV in vitro • Interferon alfa reduced viral titres in lungs of SARS-CoV-infected mice and cynomolgus macaques • Intranasal interferon beta administered before or after MERS-CoV challenge reduced viral titres in the lungs of Ad5-hDPP4 C57BL/6 and Rag1−/− mice by 10–100 fold • Subcutaneous interferon beta-1b improved outcomes of MERS-CoV-infected common marmosets • Benefits for SARS patients are uncertain • Benefits of interferon alfa-2a, interferon alfa-2b and interferon beta-1a for MERS patients are uncertain |
8,9,74,86,87,89,99,116,121,122,128,148,191,192,215 |
| Poly(I:C) | Induces interferon production | Phase II clinical trials |
• Reduced MERS-CoV load in Ad5-hDPP4 BALB/c mice • Used in Phase II clinical trials of patients with malignant gliomas |
157,193,194 | |
| Nitazoxanide | A thiazolide that induces the host innate immune response by potentiation of interferon alfa and interferon beta production by fibroblasts and activation of PKR | Marketed |
• Broad spectrum: canine CoV, IAV, IBV, RSV, PIF, Sendai virus, rhinovirus, norovirus, rotavirus, Dengue virus, JEV, YFV, HBV, HCV and HIV • Used in patients with parasitic infections and in Phase II and III clinical trials of HCV infection and influenza • Activity against human-pathogenic CoVs has yet to be determined |
195 | |
| Other host signalling pathways involved in viral replication | |||||
| Cyclophilins | Cyclosporine, alisporivir | Cyclophilin inhibitor that could modulate the interaction of cyclophilins with SARS-CoV nsp1 and the calcineurin–NFAT pathway | Marketed |
• Broad spectrum: CoVs (SARS-CoV, MERS-CoV, HCoV-NL63, HCoV-229E, and animal CoVs), HIV, HCV, HPV, vaccinia virus and VSV • Alisporivir does not have the immunosuppressive effects of cyclosporine and may therefore be a more suitable antiviral candidate |
118,119,120,200 |
| Kinase signalling pathways | Trametinib, selumetinib, everolimus, rapamycin, dasatinib and imatinib | Kinase signalling inhibitors that block the ABL1, ERK–MAPK and/or PI3K–AKT–mTOR pathways, which may block early viral entry and/or post-entry events | Marketed |
• Active against SARS-CoV and MERS-CoV • May be associated with immunopathology |
124,125 |
| Host receptors utilized by CoVs for viral entry | |||||
| ACE2 | P4 and P5 peptides and NAAE | ACE2-derived peptides or small molecules targeting ACE2 that block SARS-CoV S-mediated cell fusion | Marketed |
• Narrow spectrum: SARS-CoV • May affect important biological functions such as blood pressure regulation |
202,203 |
| DPP4 | Anti-DPP4 mAb clones 2F9 and YS110 | Anti-DPP4 mAbs that block MERS-CoV S-mediated cell fusion | Phase I clinical trial |
• Narrow spectrum: MERS-CoV • May affect important biological functions such as glucose metabolism and immunological responses • mAb clone YS110 was used in a Phase I clinical trial of patients with advanced malignancies |
102,201,227 |
| Host proteases utilized by CoVs for viral entry | |||||
| Endosomal protease (for example, cathepsins) | E64D, K11777 and the small molecule 5705213 | Cathepsin inhibitors that block endosomal protease-mediated cleavage and the endosomal entry pathway | Preclinical |
• Broad spectrum: CoVs (SARS-CoV and MERS-CoV), filoviruses (Ebola virus) and paramyxoviruses (Hendra and Nipah viruses) • Combination with TMPRSS2 inhibitors necessary for complete inhibition of MERS-CoV in vitro |
111,124,127,283 |
| Surface protease (for example, TMPRSS2) | Camostat mesylate | TMPRSS2 inhibitor that blocks the TMPRSS2-mediated cell surface entry pathway | Marketed |
• Broad spectrum: CoVs (SARS-CoV, MERS-CoV and HCoV-229E), IAV and PIF • Combination with cathepsin inhibitors is necessary for complete inhibition of MERS-CoV in vitro • Used to treat patients with chronic pancreatitis |
109,111,207,208,284,285,286 |
| Other host proteases (for example, furin) | dec-RVKR-CMK | Furin inhibitor that blocks furin-mediated cleavage of S | Preclinical | Active against MERS-CoV and may be active against other CoVs that utilize furin for S cleavage | 110 |
| Endocytosis | |||||
| Clathrin-mediated endocytosis | Chlorpromazine | An antipsychotic that also affects the assembly of clathrin-coated pits at the plasma membrane | Marketed |
• Broad spectrum: SARS-CoV, MERS-CoV, HCV and alphaviruses • Clinical benefit uncertain owing to a high EC50/Cmax ratio at the usual therapeutic dosages |
123 |
| Clathrin-mediated endocytosis | Ouabain and bufalin | ATP1A1-binding cardiotonic steroids that inhibit clathrin-mediated endocytosis | Marketed |
• Active against MERS-CoV at nanomolar concentrations in vitro • May have risk of toxicity |
209 |
| Endosomal acidification | Chloroquine | An antimalarial that sequesters protons in lysosomes to increase the intracellular pH | Marketed |
• Broad spectrum: CoVs (SARS-CoV, MERS-CoV, HCoV-229E and HCoV-OC43), HIV, flaviviruses and Ebola, Hendra and Nipah viruses in vitro • Not active against SARS-CoV-infected mice |
123,210,211,212,213,214,215 |
ACE2, angiotensin-converting enzyme 2; Ad5-hDPP4, adenovirus type 5 expressing human dipeptidyl peptidase 4; ATP1A1, ATPase subunit α1; Cmax, peak serum concentration; CoV, coronavirus; dec-RVKR-CMK, decanoyl-Arg-Val-Lys-Arg-chloromethylketone; DPP4; dipeptidyl peptidase 4; EC50, half-maximal effective concentration; ERK, extracellular signal-regulated kinase; HBV, hepatitis B virus; HCoV, human coronavirus; HCV, hepatitis C virus; HPV, human papillomavirus; IAV, influenza A virus; IBV, influenza B virus; JEV, Japanese encephalitis virus; mAb, monoclonal antibody; MAPK, mitogen-activated protein kinase; MERS, Middle East respiratory syndrome; mTOR, mammalian target of rapamycin; NAAE, N-(2-aminoethyl)-1-aziridine-ethanamine; NFAT, nuclear factor of activated T cells; nsp1, non-structural protein 1; PI3K, phosphoinositide 3-kinase; PIF, parainfluenza virus; PKR, protein kinase R; poly(I:C), polyinosinic:polycytidylic acid; RSV, respiratory syncytial virus; S, spike glycoprotein; SARS, severe acute respiratory syndrome; TMPRSS2, transmembrane protease serine 2; VSV, vesicular stomatitis virus; YFV, yellow fever virus.