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Thermal shift assay (TSA)-based drug screening strategy for rapid discovery of inhibitors against the Nsp13 helicase of SARS-CoV-2

Li et al., Animals and Zoonoses, doi:10.1016/j.azn.2024.06.001

Jul 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.

4,700+ studies for 92 treatments. c19early.org

In Vitro study showing that 11 compounds inhibited the SARS-CoV-2 helicase Nsp13, with 7 compounds inhibiting ATPase activity and 4 inhibiting RNA unwinding activity at micromolar concentrations. Authors screened 1,970 FDA-approved drugs using a thermal shift assay, identifying 26 top binders to Nsp13. Biochemical assays confirmed 7 ATPase inhibitors (verteporfin, olsalazine sodium, diclofenac, benidipine, dyclonine, methyl salicylate, butylparaben; IC₅₀ 1.07-6.55 μM) and 4 RNA unwinding inhibitors (efaproxiral, fenretinide, curcumin, wedelolactone; IC₅₀ 12.23-14.91 μM). The inhibitors were reversible and docking predicted binding to Nsp13's ATPase or RNA binding domains. Curcumin was the most promising helicase inhibitor identified.

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

24 In Silico studies1-24

21 In Vitro studies1,5,7,11,17,21,25-39

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,5,7,9-11,13,14,16,19,21,22,24,36, RNA-dependent RNA polymeraseD,11,20, ACE2E,12,13,15, nucleocapsidF,6,23, nsp10G,23, and helicaseH,26 proteins. In Vitro studies demonstrate inhibition of the spikeA,31 (and specifically the receptor binding domainB,39), M^proC,17,31,36,38, ACE2E,39, and TMPRSS2I,39 proteins. In Vitro studies demonstrate efficacy in Calu-3J,37, A549K,31, 293TL,1, HEK293-hACE2M,17,29, 293T/hACE2/TMPRSS2N,30, Vero E6O,7,11,21,29,31-33,35,37, and SH-SY5YP,28 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 cells35, 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 fibroblasts40.

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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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22. Rajagopal et al., Activity of phytochemical constituents of Curcuma longa (turmeric) and Andrographis paniculata against coronavirus (COVID-19): an in silico approach, Future Journal of Pharmaceutical Sciences, doi:10.1186/s43094-020-00126-x.springeropen.com, doi.org.

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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. 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.

k. 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.

l. 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.

m. 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.

n. 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.

o. 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.

p. 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.

Li et al., 1 Jul 2024, China, peer-reviewed, 4 authors. Contact: cryptosporida@gmail.com (corresponding author).

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

This Paper Curcumin All

Thermal shift assay (TSA)-based drug screening strategy for rapid discovery of inhibitors against the Nsp13 helicase of SARS-CoV-2

Meng Li, Jigang Yin, Chang Li, Guan Zhu

Animals and Zoonoses, doi:10.1016/j.azn.2024.06.001

Thermal shift assay (TSA)-based drug screening strategy for rapid discovery of inhibitors against the Nsp13 helicase of SARS

CRediT authorship contribution statement Meng Li played a key role in the experimental setup and data collection, and were responsible for ensuring the quality and integrity of the data obtained. In addition, Meng Li contributed to the analysis J o u r n a l P r e -p r o o f Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The author Guan Zhu and Chang Li are Editorial Board Member for Animals and Zoonoses and were not involved in the editorial review or the decision to publish this article. Declaration of interests ☐ The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. J o u r n a l P r e -p r o o f

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