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  3. The Culprit of Global Pandemic COVID-19
COVID-19 Treatments: Antiviral and Anti-inflammation

COVID-19 Treatments: Antiviral and Anti-inflammation

Antiviral

•Remdesivir and Nucleoside Analogues

•Chloroquine and its Family Members

Anti-inflammation
Antiviral Natural Products
COVID-19 Related Compound Libraries

The pandemic outbreak of coronavirus disease 2019 (COVID-19) has spread all over the world and has been a great threat to humans for absence of specific effective anti-viral treatments. It is urgent to identify effective, safe, and available treatment strategy for COVID-19.

As COVID-19 is a viral infectious disease with major symptoms of fever and pneumonia, antiviral and anti-inflammation related supportive therapies are important treatments for severe cases.

Schematic of SARS-CoV-2 infection

Schematic of SARS-CoV-2 infection[1-3]

COVID-19 in caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2). SARS-CoV-2 belongs to coronavirus (CoV) who have four main structural proteins: spike (S), membrane (M), envelope (E), and nucleocapsid (N) proteins.

After primed by a protease called TMPRSS2 (transmembrane protease, serine 2), the S protein mediates the CoV entry into host cells by attaching to a cellular receptor named ACE2, followed by fusion between virus and host cell membranes. Genome replication and subgenomic RNA transcription after entry carry on with the participation of many nonstructural proteins such as Mpro (main protease or 3CLpro), PLpro (papain-like protease) and RdRp (RNA-dependent RNA polymerase). Then the structural proteins are translated, assembled into mature virions, and released via vesicles by exocytosis.

What’s worth mentioning, the vast release of cytokines (such as IL-1β, GM-CSF, IL-6, IL-10) by the immune system in response to severe infection of SARS-CoV-2 called cytokine storm contributes largely to the mortality of COVID-19.

Antiviral

All the proteins and subcellular structures participated in the life cycle of CoVs are promising targets for treatment of disease caused by CoVs. It is inspiring that numbers of promising agents with potential of antiviral have been reported to deal with COVID-19.

Group Compound Mechanism of action
Inhibitors of viral protein synthesis Lopinavir[4]
Ritonavir[4] 		Protease inhibitor.
Inhibitors of viral RNA
polymerase/RNA synthesis		 Remdesivir[5]
GS-443902[6]
GS-443902 trisodium[6]
Favipiravir[7]
Ribavirin[8] 		Nucleoside analogue, prodrug, RdRp inhibitor.
Inhibitors of viral entry Chloroquine[5]
Chloroquine phosphate[5]
Hydroxychloroquine sulfate[5] 		Increasing endosomal pH required for virus/cell fusion, as well as interfering with the glycosylation of ACE2.
Camostat mesylate[9]
Nafamostat mesylate[10] 		Inhibiting Sprotein priming and S protein-driven cell entry of SARS-CoV-2 mediating by TMPRSS2.
Umifenovir hydrochloride[11] Might inhibit the fusion process.
Inhibitors of Mpro Ebselen[12]
Carmofur[12]
PX-12[12]
SARS-CoV-2-IN-1[13] 		Binding with Mpro of SARS-CoV-2.
Inhibitor of viral proteins trafficking Ivermectin[14] Inhibit importin α/β-mediated nuclear transport, which in turn blocks the nuclear trafficking of viral proteins.
Enhance antiviral immune response Nitazoxanide[15]
Interferon-beta 1[16] 		Regulates inflammation pathways.

Remdesivir and Nucleoside Analogues

Remdesivir is an adenosine analogue, which incorporates into nascent viral RNA chains and function as inhibitor of RdRp. Remdesivir has been reported to inhibit numbers of RNA viruses (including SARS-CoV, MERS-CoV and SARS-CoV-2) infection in cultured cells and showed effects for treating COVID-19 in clinical. Except for remdesivir, its metabolites and several nucleoside analogues are also reported to have the antiviral ability.

Condition Compound Mechanism Status
Anticancer
Nucleoside & Nucleotide
Analogues		 Gemcitabine Targets DNA polymerase Approved
5-Azacytidine Traps DNA methyltransferase Approved
Cytarabine Targets DNA polymerase Approved
Antiviral
Nucleoside & Nucleotide
Analogues		 Remdesivir[5]
GS-443902[6]
GS-443902 trisodium[5]
Remdesivir nucleoside monophosphate 		Remdesivir and its metabolites, inhibitors of RdRp. Phase III
Favipiravir Targets RNA-dependent RNA polymerase (RdRp) Approved
Tenofovir Targets nucleotide reverse transcriptase Approved
Asunaprevir Targets NS3 protease Approved
Antibacterial
Nucleoside & Nucleotide
Analogues		 Linezolid Inhibits bacterial protein synthesis Approved
Nitrofurantoin Inhibits bacterial DNA, RNA and protein synthesis Approved
Isoniazid Acts on the mycobacterial cell wall Approved

Chloroquine and Its Family Members

Chloroquine is a widely-used anti-malarial and autoimmune disease drug, has recently been reported as a potential broad spectrum antiviral drug. Chloroquine is known to block virus infection by inhibiting the fusion of virus and host cell by increasing endosomal pH and interfering the function of ACE2. Chloroquine and hydroxychloroquine are proposed to be used to treat COVID-19 in clinical trials.

  • Subfamily Members
  • Relationship
  • Mechanism of Action
  • Clinical Status and Indication
Chloroquine Subfamily
Chloroquine Representative Drug Autophagy, RNA-dependent
RNA polymerase, TLR		 Approved: Malaria, Tumor, Rheumatoid Arthritis,
COVID-19, etc
Preclinical Research: Chikungunya Virus
Didesethyl Chloroquine Major Metabolite of
Chloroquine		 Autophagy, RNA-dependent
RNA polymerase		 Preclinical Research: Malaria, Chikungunya Virus
Hydroxychloroquine Less Toxic Metabolite of
Chloroquine		 Autophagy, RNA-dependent
RNA polymerase, TLR		 Approved: Malaria, Tumor, Rheumatoid Arthritis,
COVID-19, etc
Preclinical Research: Chikungunya Virus
Cletoquine Major Active Metabolite of
Hydroxychloroquine		 Autophagy, RNA-dependent
RNA polymerase		 Preclinical Research: Chikungunya Virus,
Antirheumatic
Ferroquine Subfamily
Ferroquine Chloroquine Analog Autophagy, Ferroptosis Phase II: Malaria
Preclinical Research: Tumor, Virus
Desmethyl Ferroquine Major Metabolite of
Ferroquine		 Autophagy, RNA-dependent
RNA polymerase		 Preclinical Research: Malaria, Virus
SARS-CoV-IN 1
SARS-CoV-IN 2
SARS-CoV-IN 3 		Derivative of Ferroquine   Preclinical Research: Malaria, SARS-CoV
Other Subfamily
Primaquine Chloroquine Analog ROS Approved: Malaria, HIV
Mefloquine Chloroquine Analog Heme polymerase Approved: Malaria
Preclinical Research: Osteoporosis
Amodiaquine Chloroquine Analog Heme polymerase Approved: Malaria
Preclinical Research: Ebola Virus
N-Desethyl amodiaquine Major Active Metabolite of
Amodiaquine		   Preclinical Research: Malaria

Anti-inflammation

Current management for COVID-19 is supportive therapy as there is still no effective cure.

Respiratory failure from acute respiratory distress syndrome (ARDS) is reported to be the leading cause of mortality of COVID-19. The primary cause of ARDS is cytokine storm characterized by excessive and uncontrolled release of pro-inflammatory cytokines (such as IL-6, IL-1, IL-17, IL-2, GM-CSF) after infection. So anti-inflammation are the most important supportive therapy for patients with severe COVID-19.

Therapeutic options for anti-inflammation in patients with COVID-19 include steroids, selective cytokine blockade, JAK inhibition, and intravenous immunoglobulin.

Compound Mechanism of action
Methylprednisolone[17] Glucocorticoids suppress cytokine storm manifestations in patients with COVID-19.
Dexamethasone[18] A glucocorticoid receptor agonist and the first drug save lives by one-third among patients critically ill with COVID-19.
Anakinra[19] An interleukin-1 receptor (IL-1R) antagonist may be beneficial for treating severe COVID-19 patients.
Tocilizumab[20]
Sarilumab[21] 		Recombinant human IL-6 monoclonal antibody thus blocking IL-6 signaling and its mediated inflammatory response, as a therapeutic option against COVID-19.
Baricitinib[22] A dual inhibitor of JAK and AAK1 (AP2-associated protein kinase 1, a regulator ofendocytosis) as the possible candidate for treatment of COVID-19 because of its relative safety and high affinity.
Chloroquine
Hydroxychloroquine[5] 		CQ and HCQ can regulate immune system by affecting cell signaling and production of pro-inflammatory cytokines.
Melatonin[23] Plays a role of adjuvant medication in the regulation of immune system, inflammation and oxidation stress.

Antiviral Natural Products

Many natural products have broad-spectrum antiviral effects by inhibiting various steps in viral infection and replication. Natural products can also function as immunomodulators, suppressing inflammatory reaction. Some of them are reported to have the potential of inhibiting coronavirus and may be promising candidate agents for COVID-19. Take emodin as an example, it has been shown to inhibit the interaction of SARS-CoV S protein with its receptor ACE2[24].

Forsythia suspensa Lonicera japonica Thunb Ephedra Semen Armeniacae amarum
Isatis indigotica L Dryopteris crassirhizoma Nakai Houttuynia cordata Pogostemon cablin
Rheum Rhodiola rosea Glycyrrhiza uralensis Menthol

COVID-19 Related Compound Libraries

It is urgent to develop drugs to treat COVID-19 quickly. The drug repurposing using visual screening technology in clinical and approved compounds can greatly shorten timeline and improve the efficiency of the development of anti-COVID-19 drugs.

As mentioned above, the reported candidate drugs for COVID-19 include agents targeting viruses (such as HIV and SARS-CoV) and inflammation. It indicates that all the antiviral, anti-infection and anti-inflammation related chemicals may have the potential to be effective in treatment of COVID-19.

Compound library Description
Anti-COVID-19
Compound Library		 Chemicals with potential anti-COVID-19 activity targeted 3CL protease, Spike protein, NSP15, RdRp, PLpro and
ACE2 collected by visual screening in Drug Repurposing Compound Library (HY-L035).
Anti-Virus Compound Library Compound library containing all kinds of molecules with anti-virus activity.
Anti-Infection Compound Library Antiviral, antibacterial, antifungal and antiparasitic compound library.
Immunology/Inflammation
Compound Library		 Antiviral, antibacterial, antifungal and antiparasitic compound library.

Anti-infection:

Antibiotic Arenavirus Bacterial CMV
EBV Enterovirus Filovirus Flavivirus
Fungal HBV HCV HCV Protease
HIV HIV Protease HPV HSV
Influenza Virus Orthopoxvirus Parasite RABV
Reverse Transcriptase RSV SARS-CoV TMV
Virus Protease VSV    

References:

[1].   Azkur, A.K., et al., Immune response to SARS‐CoV‐2 and mechanisms of immunopathological changes in COVID‐19. Allergy, 2020.

[2].   Strope, J.D., C.H.C. PharmD and W.D. Figg, TMPRSS2: Potential Biomarker for COVID‐19 Outcomes. The Journal of Clinical Pharmacology, 2020. 60(7): p. 801-807.

[3].   Tay, M.Z., et al., The trinity of COVID-19: immunity, inflammation and intervention. Nature reviews. Immunology, 2020. 20(6): p. 363-374.

[4].   Lim, J., et al., Case of the Index Patient Who Caused Tertiary Transmission of Coronavirus Disease 2019 in Korea: the Application of Lopinavir/Ritonavir for the Treatment of COVID-19 Pneumonia Monitored by Quantitative RT-PCR. Journal of Korean Medical Science, 2020. 35(6).

[5].   Wang, M., et al., Remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-nCoV) in vitro. Cell Research, 2020. 30(3): p. 269-271.

[6].   Yang, K., What do we know about remdesivir drug interactions? Clinical and Translational Science, 2020.

[7].   Cai, Q., et al., Experimental Treatment with Favipiravir for COVID-19: An Open-Label Control Study. Engineering, 2020.

[8].   Elfiky, A.A., Anti-HCV, nucleotide inhibitors, repurposing against COVID-19. Life Sciences, 2020. 248: p. 117477-117477.

[9].   Hoffmann, M., et al., SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 2020. 181(2): p. 271-280.e8.

[10].   Hoffmann, M., et al., Nafamostat Mesylate Blocks Activation of SARS-CoV-2: New Treatment Option for COVID-19. Antimicrobial Agents and Chemotherapy, 2020. 64(6).

[11].   Deng, L., et al., Arbidol combined with LPV/r versus LPV/r alone against Corona Virus Disease 2019: A retrospective cohort study. Journal of Infection, 2020. 81(1): p. e1-e5.

[12].   Jin, Z., et al., Structure of Mpro from SARS-CoV-2 and discovery of its inhibitors. Nature, 2020.

[13].   Zhang, L., et al., Crystal structure of SARS-CoV-2 main protease provides a basis for design of improved α-ketoamide inhibitors. Science (American Association for the Advancement of Science), 2020. 368(6489): p. 409.

[14].   Sharun, K., et al., Ivermectin, a new candidate therapeutic against SARS-CoV-2/COVID-19. Annals of Clinical Microbiology and Antimicrobials, 2020. 19(1).

[15].   Toby Pepperrell, V.P.A.O., Review of safety and minimum pricing of nitazoxanide for potential treatment of COVID-19. Journal of Virus Eradication, 2020. 6: p. 52-60.

[16].   Hung, I.F., et al., Triple combination of interferon beta-1b, lopinavir–ritonavir, and ribavirin in the treatment of patients admitted to hospital with COVID-19: an open-label, randomised, phase 2 trial. The Lancet (British edition), 2020. 395(10238): p. 1695-1704.

[17].   Wang, Y., et al., A retrospective cohort study of methylprednisolone therapy in severe patients with COVID-19 pneumonia. Signal Transduction and Targeted Therapy, 2020. 5(1).

[18].   Ledford, H., Coronavirus Breakthrough: Dexamethasone Is First Drug Shown to Save Lives. NATURE, 2020.

[19].   Dimopoulos, G., et al., FAVORABLE ANAKINRA RESPONSES IN SEVERE COVID-19 PATIENTS WITH SECONDARY HEMOPHAGOCYTIC LYMPHOHISTIOCYTOSIS. Cell host & microbe, 2020.

[20].   Luo, P., et al., Tocilizumab treatment in COVID‐19: A single center experience. Journal of Medical Virology, 2020. 92(7): p. 814-818.

[21].   Benucci, M., et al., COVID‐19 pneumonia treated with Sarilumab: A clinical series of eight patients. Journal of Medical Virology, 2020.

[22].   Cantini, F., et al., Baricitinib therapy in COVID-19: A pilot study on safety and clinical impact. The Journal of infection, 2020.

[23].   Rui Zhang, X.W.L.N., COVID-19: Melatonin as a potential adjuvant treatment. Life Sciences, 2020. 250(117583).

[24].   Ho, T., et al., Emodin blocks the SARS coronavirus spike protein and angiotensin-converting enzyme 2 interaction. Antiviral Research, 2007. 74(2): p. 92-101.