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Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach

Singh et al., Research Square, doi:10.21203/rs.3.rs-3888947/v1

Jan 2024

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Curcumin for COVID-19

15th treatment shown to reduce risk in February 2021

^*, now with p = 0.0000000096 from 27 studies.

Lower risk for mortality, ventilation, hospitalization, progression, recovery, and viral clearance.

No treatment is 100% effective. Protocols combine treatments. ^* >10% efficacy, ≥3 studies.

5,000+ studies for 104 treatments. c19early.org

In Silico and In Vitro study including quercetin and curcumin derivatives as potential SARS-CoV-2 main protease (M^pro) inhibitors. Molecular dynamics simulations and virtual screening identified quercetin and curcumin derivatives demethoxycurcumin and hexahydrocurcumin as potential binders of M^pro. Demethoxycurcumin was tested in vitro, showing significant inhibitory activity against SARS-CoV-2, with no cytotoxicity observed.

47 preclinical studies support the efficacy of curcumin for COVID-19:

24 In Silico studies1-24

22 In Vitro studies1,5,7,11,17,21,25-40

1 In Vivo animal study5

In Silico studies predict inhibition of SARS-CoV-2 with curcumin or metabolites via binding to the spikeA,5,10,12,18,21 (and specifically the receptor binding domainB,8,11,14), M^proC,5,7,9-11,13,14,16,19,21,22,24,37, RNA-dependent RNA polymeraseD,11,20, ACE2E,12,13,15, nucleocapsidF,6,23, nsp10G,23, and helicaseH,27 proteins. In Vitro studies demonstrate inhibition of the spikeA,32 (and specifically the receptor binding domainB,40), M^proC,17,32,37,39, ACE2E,40, and TMPRSS2I,40 proteins, and inhibition of spike-ACE2 interactionJ,25. In Vitro studies demonstrate efficacy in Calu-3K,38, A549L,32, 293TM,1, HEK293-hACE2N,17,30, 293T/hACE2/TMPRSS2O,31, Vero E6P,7,11,21,30,32-34,36,38, and SH-SY5YQ,29 cells. Curcumin is predicted to inhibit the interaction between the SARS-CoV-2 spike protein receptor binding domain and the human ACE2 receptor for the delta and omicron variants8, decreases pro-inflammatory cytokines induced by SARS-CoV-2 in peripheral blood mononuclear cells36, alleviates SARS-CoV-2 spike protein-induced mitochondrial membrane damage and oxidative stress1, and may limit COVID-19 induced cardiac damage by inhibiting the NF-κB signaling pathway which mediates the profibrotic effects of the SARS-CoV-2 spike protein on cardiac fibroblasts41.

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Study covers curcumin and quercetin.

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2. Öztürkkan et al., In Silico investigation of the effects of curcuminoids on the spike protein of the omicron variant of SARS-CoV-2, Baku State University Journal of Chemistry and Material Sciences, 1:2, bsuj.bsu.edu.az/uploads/pdf/ec4204d62f7802de54e6092bf7860029.pdf.edu.az.

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17. Wu et al., Potential Mechanism of Curcumin and Resveratrol against SARS-CoV-2, Research Square, doi:10.21203/rs.3.rs-2780614/v1.researchsquare.com, doi.org.

18. Nag et al., Curcumin inhibits spike protein of new SARS-CoV-2 variant of concern (VOC) Omicron, an in silico study, Computers in Biology and Medicine, doi:10.1016/j.compbiomed.2022.105552.sciencedirect.com, doi.org.

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21. Kandeil et al., Bioactive Polyphenolic Compounds Showing Strong Antiviral Activities against Severe Acute Respiratory Syndrome Coronavirus 2, Pathogens, doi:10.3390/pathogens10060758.mdpi.com, doi.org.

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23. Suravajhala et al., Comparative Docking Studies on Curcumin with COVID-19 Proteins, Preprints, doi:10.20944/preprints202005.0439.v3.preprints.org, doi.org.

24. Sekiou et al., In-Silico Identification of Potent Inhibitors of COVID-19 Main Protease (Mpro) and Angiotensin Converting Enzyme 2 (ACE2) from Natural Products: Quercetin, Hispidulin, and Cirsimaritin Exhibited Better Potential Inhibition than Hydroxy-Chloroquine Against COVID-19 Main Protease Active Site and ACE2, ChemRxiv, doi:10.26434/chemrxiv.12181404.v1.chemrxiv.org, doi.org.

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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 M^pro, also known as 3CL^pro or nsp5, is a cysteine protease that cleaves viral polyproteins into functional units needed for replication. Inhibiting M^pro 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 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. 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.

g. Non-structural protein 10 (nsp10) serves as an RNA chaperone and stabilizes conformations of nsp12 and nsp14 in the replicase-transcriptase complex, which synthesizes new viral RNAs. Nsp10 disruption may destabilize replicase-transcriptase complex activity.

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. 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.

j. 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.

k. 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.

l. 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.

m. 293T is a human embryonic kidney cell line that can be engineered for high ACE2 expression and SARS-CoV-2 susceptibility. 293T cells are easily transfected and support high protein expression.

n. HEK293-hACE2 is a human embryonic kidney cell line with high ACE2 expression and SARS-CoV-2 susceptibility. Cells have been transfected with a plasmid to express the human ACE2 (hACE2) protein.

o. 293T/hACE2/TMPRSS2 is a human embryonic kidney cell line engineered for high ACE2 and TMPRSS2 expression, which mimics key aspects of human infection. 293T/hACE2/TMPRSS2 cells are very susceptible to SARS-CoV-2 infection.

p. 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.

q. SH-SY5Y is a human neuroblastoma cell line that exhibits neuronal phenotypes. It is commonly used as an in vitro model for studying neurotoxicity, neurodegenerative diseases, and neuronal differentiation.

Singh et al., 29 Jan 2024, preprint, 7 authors. Contact: khushboo.singh@amway.com.

In Silico studies are an important part of preclinical research, however results may be very different in vivo.

This Paper Curcumin All

Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico and cell-based approach

Khushboo Singh, J J Patten, Andrea Dimet, Robert A Davey, Stanley J Watowich, Amit Chandra, Jesse Leverett

doi:10.21203/rs.3.rs-3888947/v1

The main protease (M Pro ) of SARS-CoV-2 plays a crucial role in viral replication and is a prime target for therapeutic interventions. Phytochemicals, known for their antiviral properties, have been previously identi ed as potential M Pro inhibitors in several in silico studies. However, the e cacy of these remains in question owing to the inherent exibility of the M Pro binding site, posing challenges in selecting suitable protein structures for virtual screening. In this study, we conducted an extensive analysis of the M Pro binding pocket, utilizing molecular dynamics (MD) simulations to explore its conformational diversity. Based on pocket volume and shape-based clustering, ve representative protein conformations were selected for virtual screening. Virtual screening of a library of ~ 48,000 phytochemicals suggested 39 phytochemicals as potential M Pro inhibitors. Based on subsequent MM-GBSA binding energy calculations and ADMET property predictions, ve compounds were advanced to cell-based viral replication inhibition assays, with three compounds (demethoxycurcumin, shikonin, and withaferin A) exhibiting signi cant (EC50 < 10 uM) inhibition of SARS-CoV-2 replication. Our study provides an understanding of the binding interactions between these phytochemicals and M Pro , contributing signi cantly to the identi cation of promising M Pro inhibitors. Furthermore, beyond its impact on therapeutic development against SARS-CoV-2, this research highlights a crucial role of proper nutrition in the ght against viral infections. Phytochemical Name Docking scores Conformation 1 Conformation 2 Conformation 3 Conformation 4 Conformation 5 1,3,6-Tri-O-Galloyl-Beta-D-Glucose -7.6 -8.8 -11.1 -7.5 -10.1 2'-Acetylacteoside -8.6 -9.5 -12.1 -13.4 -7.6 2''-O-Acetylrutin -10.3 -9.6 -12.2 -10.8 -10.4 *AHDPH -8.1 -9.0 -11.6 -7.5 -9.0 Balanophotannin E -7.5 -11.0 -12.9 -9.9 -8.4 **DDHHG -9.7 -8.3 -10.9 -11.3 -8.6 ***DHMMP-TRTH-TMMO-Chr-One -9.7 -10.5 -10.7 -9.1 -9.9 Eriodictyol 7-O-Sophoroside -12.6 -9.3 -10.0 -11.1 -10.0 Forsythiaside -10.3 -12.6 -14.3 -14.6 -9.2 Hyperin 6''-[glucosyl-(1->3)-rhamnoside] -9.7 -10.9 -15.9 -12.1 -11.9 Kaempferol 3-(3R-glucosylrutinoside) -10.0 -10.6 -12.0 -11.1 -8.5 Luteolin 7-rutinoside -9.8 -9.4 -14.4 -12.0 -9.9 Narcissin -9.7 -10.5 -10.7 -9.1 -9.9 Pectolinarin -8.9 -7.7 -13.9 -8.5 -7.5 Plantagineoside C -9.4 -10.3 -13.3 -10.4 -9.3 Quercetin 3-glucoside2''-gallate -7.8 -9.2 -12.1 -10.6 -7.5 Quercetin-3-o-rutinose -12.2 -11.0 -11.1 -11.5 -11.4 Salvianolic Acid L (SAL) -9.1 -8.2 -13.3 -11.3 -7.6 Shikonin -8.1 -8.4 -8.6 -8.9 -9.5 Shimobashiric Acid C (SAC) -8.2 -8.7 -10.5 -9.6 -10. 2 *AHDPH = (3R,5R)-3-Acetoxy-5-Hydroxy-1,7-Bis(3,4-Dihydroxyphenyl)Heptane. **DDHHG = (3R,5R)-3,5-Dihydroxy-1-(3,4-Dihydroxyphenyl)-7-(4-Hydroxyphenyl)-Heptane 3-O-Beta-D-Glucopyranoside.

For a comprehensive understanding of the model speci cations, validation, and performance, please refer to the AP11.0 user manual and relevant publications 74, 75 . Cytoxicity Assay Vero cells were seeded using a multiDrop combi liquid dispenser (Thermo) into 384-well plates at a density of 500 cells/well suspended in 50 µL of media. Cells were allowed to recover and fully attach overnight (approximately 16 hours), at which point library compounds were dispensed into wells using an Echo 550 acoustic dispenser (Labcyte). A total of six nal concentrations where tested (50 µM, 25 µM, 12.5 µM, 6.25 µM, 3.125 µM, and 1.5625 µM) and wells were back lled with DMSO such that all wells contained a xed ratio of DMSO. Compounds were incubated with cells for 1 hour prior to addition of virus and then for an additional 24 hours, then xed with 10% formalin, permeabilized 0.1% Triton X-100, washed, and stained for SARS-CoV-2 N protein using a speci c antibody (Sino Biological # MM05) and uorescently labelled secondary antibody. Cells were counter stained with Hoechst 33342 to detect cell nuclei, washed, and imaged with a Cytation 1 (Biotek) automated. Each image was then analyzed with a custom work ow in Cell Pro ler (Broad Inst., Boston, MA) which involved counting of cell nuclei and infected cells. At least 4 replicates were used to construct dose response curves. Statistics and data normalization The rate index is calculated from cell counts using the following formula: Where X c..

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However, the ' 'efficacy of these remains in question owing to the inherent flexibility of the ' 'MPro binding site, posing challenges in selecting suitable protein ' 'structures for virtual screening. In this study, we conducted an extensive analysis of the ' 'MPro binding pocket, utilizing molecular dynamics (MD) simulations to ' 'explore its conformational diversity. Based on pocket volume and shape-based clustering, five ' 'representative protein conformations were selected for virtual screening. Virtual screening ' 'of a library of ~\u200948,000 phytochemicals suggested 39 phytochemicals as potential ' 'MPro inhibitors. Based on subsequent MM-GBSA binding energy calculations ' 'and ADMET property predictions, five compounds were advanced to cell-based viral replication ' 'inhibition assays, with three compounds (demethoxycurcumin, shikonin, and withaferin A) ' 'exhibiting significant (EC50\u2009<\u200910 uM) inhibition of SARS-CoV-2 replication. Our ' 'study provides an understanding of the binding interactions between these phytochemicals and ' 'MPro, contributing significantly to the identification of promising ' 'MPro inhibitors. Furthermore, beyond its impact on therapeutic ' 'development against SARS-CoV-2, this research highlights a crucial role of proper nutrition ' 'in the fight against viral infections.', 'DOI': '10.21203/rs.3.rs-3888947/v1', 'type': 'posted-content', 'created': {'date-parts': [[2024, 1, 29]], 'date-time': '2024-01-29T10:28:18Z', 'timestamp': 1706524098000}, 'source': 'Crossref', 'is-referenced-by-count': 0, 'title': 'Unlocking the potential of phytochemicals in inhibiting SARS-CoV-2 M Pro protein - An in-silico ' 'and cell-based approach', 'prefix': '10.21203', 'author': [ { 'given': 'Khushboo', 'family': 'Singh', 'sequence': 'first', 'affiliation': [{'name': 'Amway (United States)'}]}, { 'given': 'J. 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