Table 2 Representative virus-based treatment strategies for CoV infections
From: Coronaviruses — drug discovery and therapeutic options
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 | |
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 | |
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 | |
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 | |
Viral enzymes | |||||
PLpro | GRL0617, compound 4 | Inhibitors of PLpro activity | Preclinical | • Narrow spectrum • No animal or human data available | |
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 | |
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 | |
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 | ||
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 | ||
siRNA* | Short chains of dsRNA that interfere with the expression of RdRp | Preclinical | • Narrow spectrum • Optimal delivery method in humans is uncertain | ||
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 | |
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 | ||
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 | |
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 | |
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 | |
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 | |
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 | |
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 | ||
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 | |
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 | |
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 | |
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 | |
