EGCG, a Green Tea Catechin, as a Potential Therapeutic Agent for Symptomatic and Asymptomatic SARS-CoV-2 Infection

Abstract

Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has emerged to be the greatest threat to humanity in the modern world and has claimed nearly 2.2 million lives worldwide. The United States alone accounts for more than one fourth of 100 million COVID-19 cases across the globe. Although vaccination against SARS-CoV-2 has begun, its efficacy in preventing a new or repeat COVID-19 infection in immunized individuals is yet to be determined. Calls for repurposing of existing, approved, drugs that target the inflammatory condition in COVID-19 are growing. Our initial gene ontology analysis predicts a similarity between SARS-CoV-2 induced inflammatory and immune dysregulation and the pathophysiology of rheumatoid arthritis. Interestingly, many of the drugs related to rheumatoid arthritis have been found to be lifesaving and contribute to lower COVID-19 morbidity. We also performed in silico investigation of binding of epigallocatechin gallate (EGCG), a well-known catechin, and other catechins on viral proteins and identified papain-like protease protein (PLPro) as a binding partner. Catechins bind to the S1 ubiquitin-binding site of PLPro, which might inhibit its protease function and abrogate SARS-CoV-2 inhibitory function on ubiquitin proteasome system and interferon stimulated gene system. In the realms of addressing inflammation and how to effectively target SARS-CoV-2 mediated respiratory distress syndrome, we review in this article the available knowledge on the strategic placement of EGCG in curbing inflammatory signals and how it may serve as a broad spectrum therapeutic in asymptomatic and symptomatic COVID-19 patients.

Keywords: COVID-19; EGCG; ISGylation; PLPro; SARS-CoV-2; catechins; inflammation; rheumatoid arthritis; ubiquitination; vaccines.

Figure 1

Gene ontology study of coronavirus disease 2019 (COVID-19) serum biomarkers. Gene ontology studies were performed on the 18 cytokines that are the signature biomarkers of COVID-19 infection, TRAIL, M-CSF, GRO-α, G-CSF, IL-6, IL-2, β-NGF, IL-10, MCP-1, SCF, IL-15, IL-8, IL-7, IP-10, PDGF-BB, IFN-γ, IL-18 and IL-2Rα, using metascape.org. (A) Top canonical pathways associated with COVID-19 inflammatory signature. (B) Top disease identifiers of inflammatory signature. (C) Network clusters associated with the canonical signature.

Figure 2

Role of epigallocatechin gallate (EGCG) in abrogating mitogen-activated protein kinase (MAPK) and Janus kinase-signal transducer and activator of transcription protein (JAK-STAT) pathway to attenuate the production of inflammatory cytokines. EGCG inhibits IL-1β induced TRAF6-TAK1 signal transduction complex formation. EGCG inhibits phosphorylation of Threonine 184/187 at its kinase domain. Inhibition of TAK1 abrogates NF-κB entry into the nucleus to abrogate IL-1 induced IL-6 and IL-8 production. EGCG also inhibits JAK2 activation and STAT3 activation by inhibiting Ser 727 and Tyr 705 phosphorylation, respectively. STAT3 binds to EGCG which suppress it DNA binding activity.

Figure 3

Gene ontology study of interferon stimulated gene (ISG) adaptor proteins. Gene ontology studies were performed on the reported ISG adaptor proteins STAT1, RIG-I, TSG101, PKR, CHMP5, IRF3, Ubiquitin, BECN1, JAK1, Cγ1, ERK1, Parkin, IFIT1, MxA, p53, Filamin B, PCNA, β-Catenin, HIF1α, IQGAP1, UBC13, UBCH6, PP2Cβ, TRIM25, 4EHP, Cyclin D1, PML–RARα and δnp63α using metascape.org. Gene enrichment analysis identified antiviral processes as top ontology terms.

Figure 4

Role of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) papain-like protease protein (PLPro) in COVID-19 infection. SARS-CoV-2 infects cells using host ACE2 and TMPRSS2 receptors. After infection, the virus uses the host transcription machinery and transcribes its early gene containing Non-structural protein (Nsp)1, Nsp2, Nsp3 and Nsp4 as a proprotein. PLPro, a papain like protease (PLP), is autocleaved from Nsp3 protein due to its intrinsic proteolytic function. SARS-CoV-2 PLPro then cleaves Nsp1–Nsp2, Nsp2–Nsp3 and Nsp3-Nsp4 junctions of the proprotein to give rise to the individual proteins. PLPro acts like a deubiquitinase and deISGylation enzyme on endogenous host proteins to abrogate host specific innate immune response.

Figure 5

Binding of various catechins to SARS-CoV-2 PLPro protein. (A) Ligand (GRL0617) Co-crystal of PLPro (PDB ID: 7CMD). (B) Electrostatic surface of PLPro binding site (C–J) represent interaction of various catechins with the ligand binding site of PLPro. The residues in orange, cyan and black color represent H-bond, Cation-pi and hydrophobic interaction respectively. Orange dotted line represents H-bond whereas cyan dotted lines represent cation-pi interaction.