Table 2. Representative virus-based treatment strategies for CoV infections.

PowerPoint slide

Targeted viral components	Examples	Mechanism of action	Status	Comments	Refs
Viral nucleic acids
Nucleosides and/or nucleotides	Mycophenolic acid	Inhibitor of IMPDH and guanine monophosphate synthesis	Marketed	• Broad spectrum: MERS-CoV, HBV, HCV, arboviruses (JEV, WNV, YFV, dengue virus and CHIKV) • Worsened outcome in MERS-CoV-infected common marmosets • Unlikely to be useful as monotherapy, but combinatorial therapy with interferon beta-1b is synergistic in vitro	122,128,192
mRNA	Ribozyme	An antisense RNA with catalytic activity that specifically recognizes the base sequence GUC in the loop region on the mRNA of CoVs	Preclinical	• Narrow spectrum • Optimal delivery method in humans is uncertain	131
Host cell membrane-bound viral replication complex	K22	Inhibitor of membrane-bound RNA synthesis and double membrane vesicle formation	Preclinical	• Broad spectrum: SARS-CoV, MERS-CoV, HCoV-229E and animal CoVs • No animal or human data available	112
Long viral dsRNA	DRACO	A chimeric protein with a viral dsRNA-binding domain and a pro-apoptotic domain that selectively induces apoptosis in cells containing viral dsRNA	Preclinical	• Broad spectrum: adenoviruses, arenaviruses, bunyaviruses, dengue virus, IAV, picornaviruses, rhinoviruses and reoviruses • Anti-CoV activity has yet to be demonstrated	132
Viral enzymes
PLpro	GRL0617, compound 4	Inhibitors of PLpro activity	Preclinical	• Narrow spectrum • No animal or human data available	137,138,139,140
3CLpro	Lopinavir, N3, CE-5 and GRL-001	Inhibitors of 3CLpro activity	Preclinical	• Broad spectrum: SARS-CoV, MERS-CoV, HCoV-229E, HCoV-NL63 and animal CoVs • Marketed: lopinavir–ritonavir • Improved outcome of MERS-CoV-infected common marmosets • Improved outcome of SARS patients in non-randomized trials	76,77,123,128,143,144,145,146,275,276
RdRp	Ribavirin	Guanosine analogue that inhibits viral RNA synthesis and mRNA capping	Marketed	• Broad spectrum: many viral infections, especially SARS, MERS, RSV, HCV and viral haemorrhagic fevers • Active against SARS-CoV and MERS-CoV at high doses in vitro • Benefits in SARS and MERS patients are uncertain • Side effects are common and may be severe with high-dose reigmens	10,21,86,87,88,89,117,277,278,279,280
	BCX4430	Adenosine analogue that acts as a non-obligate RNA chain terminator to inhibit viral RNA polymerase function	Preclinical	• Broad spectrum: SARS-CoV, MERS-CoV, IAV, filoviruses, togaviruses, bunyaviruses, arenaviruses, paramyxoviruses, picornaviruses and flaviviruses • No animal or human data are available for CoVs	149
	Fleximer nucleoside analogues of acyclovir	Doubly flexible nucleoside analogues based on the acyclic sugar scaffold of acyclovir and the flex-base moiety in fleximers that inhibit RdRp	Preclinical	• Active against MERS-CoV and HCoV-NL63 • Further modification of existing nucleoside analogues with different fleximers is possible • No animal or human data available	150
	siRNA*	Short chains of dsRNA that interfere with the expression of RdRp	Preclinical	• Narrow spectrum • Optimal delivery method in humans is uncertain	151,152
Helicase	Bananins and 5-hydroxychromone derivatives	Inhibits helicase unwinding and ATPase activities	Preclinical	• Possibly broad spectrum: helicase is relatively conserved among CoVs • High risk of toxicity	153,154
	SSYA10-001 and ADKs	Inhibits helicase unwinding without affecting ATPase activity	Preclinical	• Broad spectrum: SARS-CoV, MERS-CoV and animal CoVs • Likely to be less toxic than bananins and 5-hydroxychromone derivatives	155,156,281
Viral spike glycoprotein
RBD of the S1 subunit of S	MERS-4, MERS-27, m336, m337, m338, REGN3051 and REGN3048 mAbs	mAbs against the RBD of the S1 subunit that block virus–host cell binding	Preclinical	• Narrow spectrum • May reduce the need for convalescent-phase plasma therapy • Protective effects demonstrated in animal models	94,95,96,97,100,160,161,162
S2 subunit of S	HR2P and P1 peptides	Antiviral peptides that inhibit fusion of S with host cell receptor	Preclinical	• Narrow spectrum • Enfuvirtide, an anti-HIV antiviral peptide fusion inhibitor, has been successfully marketed	92,93,99,160,161,162
Oligosaccharides on S	Griffithsin	A carbohydrate-binding agent that specifically binds to oligosaccharides on S, thereby blocking virus–host cell binding	Preclinical	• Broad spectrum: SARS-CoV, MERS-CoV, HCoV-229E, HCoV-OC43, HIV, HCV and Ebola virus • Well tolerated in rodents	173,174
S expression	siRNA*	Short chains of dsRNA that interfere with the expression of SARS-CoV S	Preclinical	• Narrow spectrum • SARS-CoV-infected rhesus macaques had better clinical, virological, and histological parameters • Optimal delivery method in humans is uncertain	169,170,171,172
Viral envelope, membrane, nucleocapsid and accessory proteins
E	siRNA*	Short chains of dsRNA that interfere with the expression of SARS-CoV E	Preclinical	• Narrow spectrum • Optimal delivery method in humans is uncertain	179
	Hexamethylene amiloride	Viroporin inhibitor that inhibits the ion channel activity of CoV E	Preclinical	• Inhibited ion channel activities of SARS-CoV, HCoV-229E and some animal CoVs • Analogue of the potassium-sparing diuretic drug amiloride	181,182
M	siRNA*	Short chains of dsRNA that interfere with the expression of SARS-CoV M	Preclinical	• Narrow spectrum • Optimal delivery method in humans is uncertain	179
N	PJ34, intrabodies‡ and siRNA*	Reduces the RNA-binding affinity of N and viral replication	Preclinical	• Narrow spectrum • Optimal delivery method in humans is uncertain	179,183,282
Accessory proteins	siRNA*	Short chains of dsRNA that interfere with the expression of proteins from SARS-CoV ORF3a, ORF7a and ORF7b	Preclinical	• Narrow spectrum • Optimal delivery method in humans is uncertain	180
Lipid membrane	LJ001 and JL103	Membrane-binding photosensitizers that induce singlet oxygen modifications of specific phospholipids	Preclinical	• Broad spectrum: enveloped viruses (IAV, filoviruses, poxviruses, arenaviruses, bunyaviruses, paramyxoviruses, flaviviruses and HIV-1) • Anti-CoV activity has yet to be demonstrated	184,185,186,187

3CLpro, 3C-like protease; ADK, aryl diketoacid; CHIKV, Chikungunya virus; CoV, coronavirus; DRACO, double-stranded RNA activated caspase oligomerizer; dsRNA, double-stranded RNA; E, envelope protein; HBV, hepatitis B virus; HCoV, human coronavirus; HCV, hepatitis C virus; IAV, influenza A virus; IMPDH, inosine-monophosphate dehydrogenase; JEV, Japanese encephalitis virus; M, membrane protein; mAb, monoclonal antibody; MERS, Middle East respiratory syndrome; N, nucleocapsid protein; ORF, open reading frame; PLpro, papain-like protease; RBD, receptor-binding domain; RdRp, RNA-dependent RNA polymerase; RSV, respiratory syncytial virus; S, spike glycoprotein; SARS, severe acute respiratory syndrome; siRNA, small interfering RNA; WNV, West Nile virus; YFV, yellow fever virus.

*Only siRNAs that have been evaluated in published reports are included. siRNAs directed against other parts of the CoV genome would also be expected to diminish the accumulation or translation of genomic and upstream subgenomic RNAs.

^‡Intrabodies are antibodies that work within the cell to bind to intracellular proteins.