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@CovidAnalysis
 

Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19

Xu et al., Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2301775120, Apr 2023
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Quercetin for COVID-19
25th treatment shown to reduce risk in July 2021, now with p = 0.002 from 12 studies.
Lower risk for ICU, hospitalization, recovery, cases, and viral clearance.
No treatment is 100% effective. Protocols combine treatments.
5,500+ studies for 121 treatments. c19early.org
In Vitro study of compounds from Huashi Baidu (Q-14), showing dose-dependent inhibition of SARS-CoV-2 with quercetin. Authors also perform a mouse study showing that Q-14 decreases SARS-CoV-2 viral load and reduces pulmonary inflammation.
Among 60 compounds, six (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) showed dose-dependent inhibition of SARS-CoV-2, including two Mpro inhibitors (echinatin and quercetin) and two RdRp inhibitors (glycyrrhisoflavone and licoisoflavone A).
Followup studies1,2 collectively show that quercetin and echinatin had only weak SARS-CoV-2 protease inhibition in SDS-PAGE assays2, but false positive FRET results from MCA-AVLQ quenching1,2. Authors note that the compounds may act via other targets to achieve reported anti-COVID-19 effects2, and underscore the importance of meticulous validation with multiple assays when identifying SARS-CoV-2 protease inhibitors1,2.
Bioavailability. Quercetin has low bioavailability and studies typically use advanced formulations to improve bioavailability which may be required to reach therapeutic concentrations.
78 preclinical studies support the efficacy of quercetin for COVID-19:
47 In Silico studies3-49
25 In Vitro studies3-6,9,19,23,25,29,46,50-64
6 In Vivo animal studies9,23,57,60,65,66
In Silico studies predict inhibition of SARS-CoV-2, or minimization of side effects, with quercetin or metabolites via binding to the spikeA,6,7,13,14,26,28,29,31,34,42,43,45,46,67, MproB,6,7,11,13,15,17,19,21,22,24,27,28,31,34,38,40-42,46-49,68, RNA-dependent RNA polymeraseC,5-7,13,36, PLproD,7,41,49, ACE2E,26,27,31,32,41,45, TMPRSS2F,26, nucleocapsidG,7, helicaseH,7,33,38, endoribonucleaseI,43, NSP16/10J,10, cathepsin LK,30, Wnt-3L,26, FZDM,26, LRP6N,26, ezrinO,44, ADRPP,42, NRP1Q,45, EP300R,20, PTGS2S,27, HSP90AA1T,20,27, matrix metalloproteinase 9U,35, IL-6V,25,39, IL-10W,25, VEGFAX,39, and RELAY,39 proteins, and inhibition of spike-ACE2 interactionZ,4. In Vitro studies demonstrate inhibition of the MproB,19,51,56,64 protein, and inhibition of spike-ACE2 interactionZ,52. In Vitro studies demonstrate efficacy in Calu-3AA,55, A549AB,25, HEK293-ACE2+AC,63, Huh-7AD,29, Caco-2AE,54, Vero E6AF,23,46,54, mTECAG,57, RAW264.7AH,57, and HLMECAI,4 cells. Animal studies demonstrate efficacy in K18-hACE2 miceAJ,60, db/db miceAK,57,66, BALB/c miceAL,65, and rats23. Quercetin reduced proinflammatory cytokines and protected lung and kidney tissue against LPS-induced damage in mice65, inhibits LPS-induced cytokine storm by modulating key inflammatory and antioxidant pathways in macrophages9, and inhibits SARS-CoV-2 ORF3a ion channel activity, which contributes to viral pathogenicity and cytotoxicity59.
Important missing comments or errors? Let us know.
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 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.
c. 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.
d. 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.
e. 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.
f. 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.
g. 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.
h. 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.
i. 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.
j. 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.
k. 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.
l. 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.
m. 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.
n. 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.
o. 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.
p. 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.
q. 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.
r. 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.
s. 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.
t. 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.
u. 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.
v. 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.
w. 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.
x. 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.
y. 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.
z. 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.
aa. 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.
ab. 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.
ac. HEK293-ACE2+ is a human embryonic kidney cell line engineered for high ACE2 expression and SARS-CoV-2 susceptibility.
ad. Huh-7 cells were derived from a liver tumor (hepatoma).
ae. 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.
af. 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.
ag. mTEC is a mouse tubular epithelial cell line.
ah. RAW264.7 is a mouse macrophage cell line.
ai. 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.
aj. A mouse model expressing the human ACE2 receptor under the control of the K18 promoter.
ak. 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.
al. A mouse model commonly used in infectious disease and cancer research due to higher immune response and susceptibility to infection.
Xu et al., 24 Apr 2023, China, peer-reviewed, 33 authors. Contact: gaof@im.ac.cn, huangluqi01@126.com.
In Vitro studies are an important part of preclinical research, however results may be very different in vivo.
This PaperQuercetinAll
Bioactive compounds from Huashi Baidu decoction possess both antiviral and anti-inflammatory effects against COVID-19
Haiyu Xu, Shufen Li, Jiayuan Liu, Jinlong Cheng, Liping Kang, Weijie Li, Yute Zhong, Chaofa Wei, Lifeng Fu, Jianxun Qi, Yulan Zhang, Miaomiao You, Zhenxing Zhou, Chongtao Zhang, Haixia Su, Sheng Yao, Zhaoyin Zhou, Yulong Shi, Ran Deng, Qi Lv, Fengdi Li, Feifei Qi, Jie Chen, Siqin Zhang, Xiaojing Ma, Zhijian Xu, Shao Li, Yechun Xu, Ke Peng, Yi Shi, Hualiang Jiang, George F Gao, Luqi Huang
Proceedings of the National Academy of Sciences, doi:10.1073/pnas.2301775120
Significance Huashi Baidu decoction (Q-14), a famous traditional Chinese medicine decoction for COVID-19, has good effects on SARS-CoV-2 RNA clearance, promoting lung lesion opacity absorption, reducing inflammation, and ameliorating flu-like symptoms based on a series of clinical trials, having potent antiviral and antiinflammatory effects. However, due to the lack of systematic and in-depth research, little significant progress has been made in the study of TCMT-NDRD of HBF for COVID-19 management. Therefore, the aim of the current study was to identify key antiviral and anti-inflammatory bioactive compounds from HBF based on an integrative pharmacological strategy. These findings will greatly stimulate the traditional Chinese medicine theory-driven natural drug discovery against COVID-19 and promote the modern research of Chinese medicine.
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DOI record: { "DOI": "10.1073/pnas.2301775120", "ISSN": [ "0027-8424", "1091-6490" ], "URL": "http://dx.doi.org/10.1073/pnas.2301775120", "abstract": "<jats:p>\n The coronavirus disease 2019 (COVID-19) pandemic is an ongoing global health concern, and effective antiviral reagents are urgently needed. Traditional Chinese medicine theory-driven natural drug research and development (TCMT-NDRD) is a feasible method to address this issue as the traditional Chinese medicine formulae have been shown effective in the treatment of COVID-19. Huashi Baidu decoction (Q-14) is a clinically approved formula for COVID-19 therapy with antiviral and anti-inflammatory effects. Here, an integrative pharmacological strategy was applied to identify the antiviral and anti-inflammatory bioactive compounds from Q-14. Overall, a total of 343 chemical compounds were initially characterized, and 60 prototype compounds in Q-14 were subsequently traced in plasma using ultrahigh-performance liquid chromatography with quadrupole time-of-flight mass spectrometry. Among the 60 compounds, six compounds (magnolol, glycyrrhisoflavone, licoisoflavone A, emodin, echinatin, and quercetin) were identified showing a dose-dependent inhibition effect on the SARS-CoV-2 infection, including two inhibitors (echinatin and quercetin) of the main protease (M\n <jats:sup>pro</jats:sup>\n ), as well as two inhibitors (glycyrrhisoflavone and licoisoflavone A) of the RNA-dependent RNA polymerase (RdRp). Meanwhile, three anti-inflammatory components, including licochalcone B, echinatin, and glycyrrhisoflavone, were identified in a SARS-CoV-2-infected inflammatory cell model. In addition, glycyrrhisoflavone and licoisoflavone A also displayed strong inhibitory activities against cAMP-specific 3′,5′-cyclic phosphodiesterase 4 (PDE4). Crystal structures of PDE4 in complex with glycyrrhisoflavone or licoisoflavone A were determined at resolutions of 1.54 Å and 1.65 Å, respectively, and both compounds bind in the active site of PDE4 with similar interactions. These findings will greatly stimulate the study of TCMT-NDRD against COVID-19.\n </jats:p>", "alternative-id": [ "10.1073/pnas.2301775120" ], "assertion": [ { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Received", "name": "received", "order": 0, "value": "2023-02-02" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Accepted", "name": "accepted", "order": 1, "value": "2023-03-14" }, { "group": { "label": "Publication History", "name": "publication_history" }, "label": "Published", "name": "published", "order": 2, "value": "2023-04-24" } ], "author": [ { "affiliation": [ { "name": "Institute of Chinese Materia Medica, Academy of Chinese Medical Sciences, Beijing 100700, China" } ], "family": "Xu", "given": "Haiyu", "sequence": "first" }, { "affiliation": [ { "name": "State Key Laboratory of Virology, Center for Antiviral Research, Wuhan Institute of Virology, Chinese Academy of Sciences, Wuhan 430207, China" } ], "family": "Li", "given": "Shufen", "sequence": "additional" }, { "ORCID": "http://orcid.org/0000-0003-4062-5278", "affiliation": [ { "name": "State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China" } ], "authenticated-orcid": false, "family": "Liu", "given": "Jiayuan", "sequence": "additional" }, { "affiliation": [ { "name": "Chinese Academy of Sciences (CAS) Key Laboratory of Pathogen Microbiology and Immunology, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China" } ], "family": "Cheng", "given": "Jinlong", "sequence": "additional" }, { "affiliation": [ { "name": "State Key Laboratory of Dao-di Herbs, National Resource Center for Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing 100700, China" } ], "family": "Kang", "given": "Liping", "sequence": "additional" }, { "affiliation": [ { "name": "Institute of Chinese Materia Medica, Academy of Chinese 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