Inhibition of SARS-CoV-2 3CLpro by chemically modified tyrosinase from Agaricus bisporus

Aguilera-Rodriguez et al., RSC Medicinal Chemistry, doi:10.1039/D4MD00289J, Sep 2024
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In vitro study showing that a purified tyrosinase enzyme from the mushroom Agaricus bisporus, chemically modified with polymers, inhibited SARS-CoV-2 3CLpro protease activity and viral replication in Vero E6 cells. The tyrosinase bioconjugate with dextran-aspartic acid (6 kDa) polymer showed the highest 3CLpro inhibition, with an IC50 of 2.5 μg/ml and IC90 of 5 μg/ml. This bioconjugate reduced SARS-CoV-2 viral load by 88% at 100 μg/mL after 48 hours in Vero E6 cells, with no observed cytotoxicity. Authors propose that these chemically modified tyrosinase enzymes could be promising antiviral protein therapeutics against SARS-CoV-2. Quercetin was used as a positive control and showed an IC50 of 6.3 μg/ml.
Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.
87 preclinical studies support the efficacy of quercetin for COVID-19:
52 in silico studies1-52
29 in vitro studies1,3,4,6-8,11,21,26,28,32,49,53-69
6 in vivo animal studies11,26,61,64,70,71
In silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,8,9,15,16,29,31,32,34,37,45,46,48,49,72 (and specifically the receptor binding domainB,5), MproC,4,5,8,9,13,15,17,19,21,23,25,27,30,31,34,37,41,43-45,49-52,69, RNA-dependent RNA polymeraseD,5,7-9,15,39, PLproE,9,44,52, ACE2F,24,29,30,34,35,44,48, TMPRSS2G,29, nucleocapsidH,9, helicaseI,9,36,41, endoribonucleaseJ,46, NSP16/10K,12, cathepsin LL,33, Wnt-3M,29, FZDN,29, LRP6O,29, ezrinP,47, ADRPQ,45, NRP1R,48, EP300S,22, PTGS2T,30, HSP90AA1U,22,30, matrix metalloproteinase 9V,38, IL-6W,28,42, IL-10X,28, VEGFAY,42, and RELAZ,42 proteins, and inhibition of spike-ACE2 interactionAA,6. In vitro studies demonstrate inhibition of the MproC,21,55,60,68 protein, and inhibition of spike-ACE2 interactionAA,56. In vitro studies demonstrate efficacy in Calu-3AB,59, A549AC,28, HEK293-ACE2+AD,67, Huh-7AE,32, Caco-2AF,58, Vero E6AG,26,49,58, mTECAH,61, RAW264.7AI,61, and HLMECAJ,6 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAK,64, db/db miceAL,61,71, BALB/c miceAM,70, and rats26. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice70, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages11, may block ACE2-spike interaction and NLRP3 inflammasome, limiting viral entry and inflammation2, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity63.
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a. The trimeric spike (S) protein is a glycoprotein that mediates viral entry by binding to the host ACE2 receptor, is critical for SARS-CoV-2's ability to infect host cells, and is a target of neutralizing antibodies. Inhibition of the spike protein prevents viral attachment, halting infection at the earliest stage.
b. The receptor binding domain is a specific region of the spike protein that binds ACE2 and is a major target of neutralizing antibodies. Focusing on the precise binding site allows highly specific disruption of viral attachment with reduced potential for off-target effects.
c. The main protease or Mpro, also known as 3CLpro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting Mpro disrupts the SARS-CoV-2 lifecycle within the host cell, preventing the creation of new copies.
d. RNA-dependent RNA polymerase (RdRp), also called nsp12, is the core enzyme of the viral replicase-transcriptase complex that copies the positive-sense viral RNA genome into negative-sense templates for progeny RNA synthesis. Inhibiting RdRp blocks viral genome replication and transcription.
e. The papain-like protease (PLpro) has multiple functions including cleaving viral polyproteins and suppressing the host immune response by deubiquitination and deISGylation of host proteins. Inhibiting PLpro may block viral replication and help restore normal immune responses.
f. The angiotensin converting enzyme 2 (ACE2) protein is a host cell transmembrane protein that serves as the cellular receptor for the SARS-CoV-2 spike protein. ACE2 is expressed on many cell types, including epithelial cells in the lungs, and allows the virus to enter and infect host cells. Inhibition may affect ACE2's physiological function in blood pressure control.
g. Transmembrane protease serine 2 (TMPRSS2) is a host cell protease that primes the spike protein, facilitating cellular entry. TMPRSS2 activity helps enable cleavage of the spike protein required for membrane fusion and virus entry. Inhibition may especially protect respiratory epithelial cells, buy may have physiological effects.
h. The nucleocapsid (N) protein binds and encapsulates the viral genome by coating the viral RNA. N enables formation and release of infectious virions and plays additional roles in viral replication and pathogenesis. N is also an immunodominant antigen used in diagnostic assays.
i. The helicase, or nsp13, protein unwinds the double-stranded viral RNA, a crucial step in replication and transcription. Inhibition may prevent viral genome replication and the creation of new virus components.
j. The endoribonuclease, also known as NendoU or nsp15, cleaves specific sequences in viral RNA which may help the virus evade detection by the host immune system. Inhibition may hinder the virus's ability to mask itself from the immune system, facilitating a stronger immune response.
k. The NSP16/10 complex consists of non-structural proteins 16 and 10, forming a 2'-O-methyltransferase that modifies the viral RNA cap structure. This modification helps the virus evade host immune detection by mimicking host mRNA, making NSP16/10 a promising antiviral target.
l. Cathepsin L is a host lysosomal cysteine protease that can prime the spike protein through an alternative pathway when TMPRSS2 is unavailable. Dual targeting of cathepsin L and TMPRSS2 may maximize disruption of alternative pathways for virus entry.
m. Wingless-related integration site (Wnt) ligand 3 is a host signaling molecule that activates the Wnt signaling pathway, which is important in development, cell growth, and tissue repair. Some studies suggest that SARS-CoV-2 infection may interfere with the Wnt signaling pathway, and that Wnt3a is involved in SARS-CoV-2 entry.
n. The frizzled (FZD) receptor is a host transmembrane receptor that binds Wnt ligands, initiating the Wnt signaling cascade. FZD serves as a co-receptor, along with ACE2, in some proposed mechanisms of SARS-CoV-2 infection. The virus may take advantage of this pathway as an alternative entry route.
o. Low-density lipoprotein receptor-related protein 6 is a cell surface co-receptor essential for Wnt signaling. LRP6 acts in tandem with FZD for signal transduction and has been discussed as a potential co-receptor for SARS-CoV-2 entry.
p. The ezrin protein links the cell membrane to the cytoskeleton (the cell's internal support structure) and plays a role in cell shape, movement, adhesion, and signaling. Drugs that occupy the same spot on ezrin where the viral spike protein would bind may hindering viral attachment, and drug binding could further stabilize ezrin, strengthening its potential natural capacity to impede viral fusion and entry.
q. The Adipocyte Differentiation-Related Protein (ADRP, also known as Perilipin 2 or PLIN2) is a lipid droplet protein regulating the storage and breakdown of fats in cells. SARS-CoV-2 may hijack the lipid handling machinery of host cells and ADRP may play a role in this process. Disrupting ADRP's interaction with the virus may hinder the virus's ability to use lipids for replication and assembly.
r. Neuropilin-1 (NRP1) is a cell surface receptor with roles in blood vessel development, nerve cell guidance, and immune responses. NRP1 may function as a co-receptor for SARS-CoV-2, facilitating viral entry into cells. Blocking NRP1 may disrupt an alternative route of viral entry.
s. EP300 (E1A Binding Protein P300) is a transcriptional coactivator involved in several cellular processes, including growth, differentiation, and apoptosis, through its acetyltransferase activity that modifies histones and non-histone proteins. EP300 facilitates viral entry into cells and upregulates inflammatory cytokine production.
t. Prostaglandin G/H synthase 2 (PTGS2, also known as COX-2) is an enzyme crucial for the production of inflammatory molecules called prostaglandins. PTGS2 plays a role in the inflammatory response that can become severe in COVID-19 and inhibitors (like some NSAIDs) may have benefits in dampening harmful inflammation, but note that prostaglandins have diverse physiological functions.
u. Heat Shock Protein 90 Alpha Family Class A Member 1 (HSP90AA1) is a chaperone protein that helps other proteins fold correctly and maintains their stability. HSP90AA1 plays roles in cell signaling, survival, and immune responses. HSP90AA1 may interact with numerous viral proteins, but note that it has diverse physiological functions.
v. Matrix metalloproteinase 9 (MMP9), also called gelatinase B, is a zinc-dependent enzyme that breaks down collagen and other components of the extracellular matrix. MMP9 levels increase in severe COVID-19. Overactive MMP9 can damage lung tissue and worsen inflammation. Inhibition of MMP9 may prevent excessive tissue damage and help regulate the inflammatory response.
w. The interleukin-6 (IL-6) pro-inflammatory cytokine (signaling molecule) has a complex role in the immune response and may trigger and perpetuate inflammation. Elevated IL-6 levels are associated with severe COVID-19 cases and cytokine storm. Anti-IL-6 therapies may be beneficial in reducing excessive inflammation in severe COVID-19 cases.
x. The interleukin-10 (IL-10) anti-inflammatory cytokine helps regulate and dampen immune responses, preventing excessive inflammation. IL-10 levels can also be elevated in severe COVID-19. IL-10 could either help control harmful inflammation or potentially contribute to immune suppression.
y. Vascular Endothelial Growth Factor A (VEGFA) promotes the growth of new blood vessels (angiogenesis) and has roles in inflammation and immune responses. VEGFA may contribute to blood vessel leakiness and excessive inflammation associated with severe COVID-19.
z. RELA is a transcription factor subunit of NF-kB and is a key regulator of inflammation, driving pro-inflammatory gene expression. SARS-CoV-2 may hijack and modulate NF-kB pathways.
aa. The interaction between the SARS-CoV-2 spike protein and the human ACE2 receptor is a primary method of viral entry, inhibiting this interaction can prevent the virus from attaching to and entering host cells, halting infection at an early stage.
ab. Calu-3 is a human lung adenocarcinoma cell line with moderate ACE2 and TMPRSS2 expression and SARS-CoV-2 susceptibility. It provides a model of the human respiratory epithelium, but many not be ideal for modeling early stages of infection due to the moderate expression levels of ACE2 and TMPRSS2.
ac. A549 is a human lung carcinoma cell line with low ACE2 expression and SARS-CoV-2 susceptibility. Viral entry/replication can be studied but the cells may not replicate all aspects of lung infection.
ad. HEK293-ACE2+ is a human embryonic kidney cell line engineered for high ACE2 expression and SARS-CoV-2 susceptibility.
ae. Huh-7 cells were derived from a liver tumor (hepatoma).
af. Caco-2 cells come from a colorectal adenocarcinoma (cancer). They are valued for their ability to form a polarized cell layer with properties similar to the intestinal lining.
ag. Vero E6 is an African green monkey kidney cell line with low/no ACE2 expression and high SARS-CoV-2 susceptibility. The cell line is easy to maintain and supports robust viral replication, however the monkey origin may not accurately represent human responses.
ah. mTEC is a mouse tubular epithelial cell line.
ai. RAW264.7 is a mouse macrophage cell line.
aj. HLMEC (Human Lung Microvascular Endothelial Cells) are primary endothelial cells derived from the lung microvasculature. They are used to study endothelial function, inflammation, and viral interactions, particularly in the context of lung infections such as SARS-CoV-2. HLMEC express ACE2 and are susceptible to SARS-CoV-2 infection, making them a relevant model for studying viral entry and endothelial responses in the lung.
ak. A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.
al. A mouse model of obesity and severe insulin resistance leading to type 2 diabetes due to a mutation in the leptin receptor gene that impairs satiety signaling.
am. A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
Aguilera-Rodriguez et al., 16 Sep 2024, peer-reviewed, 8 authors. Contact: josempalomo@icp.csic.es.
In vitro studies are an important part of preclinical research, however results may be very different in vivo.
Inhibition of SARS-CoV-2 3CLpro by chemically modified tyrosinase from Agaricus bisporus
David Aguilera-Rodriguez, David Ortega-Alarcon, Angela Vazquez-Calvo, Veronica Ricci, Olga Abian, Adrian Velazquez-Campoy, Antonio Alcami, Jose M Palomo
RSC Medicinal Chemistry, doi:10.1039/d4md00289j
Antiviral compounds are crucial to controlling the SARS-CoV-2 pandemic. Approved drugs have been tested for their efficacy against COVID-19, and new pharmaceuticals are being developed as a complementary tool to vaccines. In this work, a cheap and fast purification method for natural tyrosinase from Agaricus bisporus (AbTyr) fresh mushrooms was developed to evaluate the potential of this enzyme as a therapeutic protein via the inhibition of SARS-CoV-2 3CLpro protease activity in vitro. AbTyr showed a mild inhibition of 3CLpro. Thus, different variants of this protein were synthesized through chemical modifications, covalently binding different tailor-made glycans and peptides to the amino terminal groups of the protein. These new tyrosinase conjugates were purified and characterized through circular dichroism and fluorescence spectroscopy analyses, and their stability was evaluated under different conditions. Subsequently, all these tyrosinase conjugates were tested for 3CLpro protease inhibition. From them, the conjugate between tyrosinase and a dextran-aspartic acid (6 kDa) polymer showed the highest inhibition, with an IC 50 of 2.5 μg ml -1 and IC 90 of 5 μg ml -1 , with no cytotoxicity activity by polymer insertion. Finally, SARS-CoV-2 virus infection was studied. It was found that this new AbTyr-Dext6000 protein showed an 80% decrease in viral load. These results show the capacity of these tyrosinase bioconjugates as potential therapeutic proteins, opening the possibility of extension and applicability against other different viruses.
Conflicts of interest There is no conflict of interest to declare.
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