Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations

Jitobaom et al., BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8 (date from preprint)

Jun 2022

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In Vitro study showing a strong synergistic effect of combinations of ivermectin, niclosamide, and chloroquine, with >10x reduction in IC₅₀ compared to individual drugs.

9 preclinical studies support the efficacy of niclosamide for COVID-19:

1 In Silico study1

8 In Vitro studies2-9

In Silico studies predict inhibition of SARS-CoV-2 with niclosamide or metabolites via binding to the spikeA,1, M^proB,1, RNA-dependent RNA polymeraseC,1, PLproD,1, nucleocapsidE,1, and helicaseF,1 proteins. Niclosamide inhibits endolysosomal acidification and suppresses TLR3-mediated pro-inflammatory signaling in human small airway epithelial cells stimulated with TLR3 agonists mimicking viral RNA2, modulates host lipid metabolism and reduces infectious SARS-CoV-2 virion production in Vero E6 cells4, reduces CD147 protein levels and inhibits SARS-CoV-2-induced upregulation of CD147 in A549-ACE2 cells, including the highly glycosylated form of CD147 which has been implicated in COVID-19 disease progression and post-COVID-19 cardiac complications5, blocked the formation of syncytia mediated by SARS-CoV-2 spike protein pseudovirus-producing cells6, may reduce inflammation, NLRP3 formation, and caspase-1 activity9, may inhibit viral uncoating, replication, and assembly via disruption of pH gradients and reduced ATP production in host cells8, and shows strong synergy when combined with ivermectin7.

Important missing comments or errors? Let us know.

Study covers ivermectin and niclosamide.

1. Haque et al., Exploring potential therapeutic candidates against COVID-19: a molecular docking study, Discover Molecules, doi:10.1007/s44345-024-00005-5.springer.com, doi.org.

2. Pejler et al., Blockade of endolysosomal acidification suppresses TLR3-mediated pro-inflammatory signaling in airway epithelial cells, Journal of Allergy and Clinical Immunology, doi:10.1016/j.jaci.2024.05.031.sciencedirect.com, doi.org.

3. Walia et al., SARS-CoV-2 virulence factor ORF3a blocks lysosome function by modulating TBC1D5-dependent Rab7 GTPase cycle, Nature Communications, doi:10.1038/s41467-024-46417-2.nature.com, doi.org.

4. Garrett et al., Niclosamide as a chemical probe for analyzing SARS-CoV-2 modulation of host cell lipid metabolism, Frontiers in Microbiology, doi:10.3389/fmicb.2023.1251065.frontiersin.org, doi.org.

5. Yang et al., Repurposing Niclosamide as a Novel Anti-SARS-CoV-2 Drug by Restricting Entry Protein CD147, Biomedicines, doi:10.3390/biomedicines11072019.mdpi.com, doi.org.

6. Sheng et al., A pseudovirus-based method to dynamically mimic SARS-CoV-2-associated cell-to-cell fusion and transmission, Acta Biochimica et Biophysica Sinica, doi:10.3724/abbs.2023129.scichina.com, doi.org.

7. Jitobaom et al., Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations, BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8.biomedcentral.com, doi.org.

8. Needham, D., The pH Dependence of Niclosamide Solubility, Dissolution, and Morphology: Motivation for Potentially Universal Mucin-Penetrating Nasal and Throat Sprays for COVID19, its Variants and other Viral Infections, Pharmaceutical Research, doi:10.1007/s11095-021-03112-x.springer.com, doi.org.

9. Munson et al., Niclosamide and ivermectin modulate caspase-1 activity and proinflammatory cytokine secretion in a monocytic cell line, British Society For Nanomedicine Early Career Researcher Summer Meeting, 2021, web.archive.org/web/20230401070026/https://michealmunson.github.io/COVID.pdf.archive.org.

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 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.

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 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.

f. 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.

Jitobaom et al., 18 Jun 2022, peer-reviewed, 8 authors. Contact: prasert.aue@mahidol.ac.th (corresponding author).

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

This Paper Niclosamide All

Synergistic anti-SARS-CoV-2 activity of repurposed anti-parasitic drug combinations

Kunlakanya Jitobaom, Chompunuch Boonarkart, Suwimon Manopwisedjaroen, Nuntaya Punyadee, Suparerk Borwornpinyo, Arunee Thitithanyanont, Panisadee Avirutnan, Prasert Auewarakul

BMC Pharmacology and Toxicology, doi:10.1186/s40360-022-00580-8

Background: COVID-19 pandemic has claimed millions of lives and devastated the health service system, livelihood, and economy in many countries worldwide. Despite the vaccination programs in many countries, the spread of the pandemic continues, and effective treatment is still urgently needed. Although some antiviral drugs have been shown to be effective, they are not widely available. Repurposing of anti-parasitic drugs with in vitro anti-SARS-CoV-2 activity is a promising approach being tested in many clinical trials. Combination of these drugs is a plausible way to enhance their effectiveness. Methods: The in vitro anti-SARS-CoV-2 activity of combinations of niclosamide, ivermectin and chloroquine were evaluated in Vero E6 and lung epithelial cells, Calu-3. Results: All the two-drug combinations showed higher potency resulting in up to 4-fold reduction in the half maximal inhibitory concentration (IC 50 ) values compared to individual drugs. Among these combinations, niclosamideivermectin achieved the highest inhibitory level of over 99%. Combination synergy analysis showed niclosamideivermectin combination to have the best synergy score with a mean Loewe synergy score of 4.28 and a peak synergy score of 24.6 in Vero E6 cells and a mean Loewe synergy score of 3.82 and a peak synergy score of 10.86 in Calu-3 cells. Conclusions: The present study demonstrated the benefit of drug combinations on anti-SARS-CoV-2 activity. Niclosamide and ivermectin showed the best synergistic profile and should be further tested in clinical trials.

Abbreviations Supplementary Information The online version contains supplementary material available at https:// doi. org/ 10. 1186/ s40360-022-00580-8. Additional file 1. Authors' contributions KJ performed drug treatment experiments, viral quantifications, analysis and was a major contributor in writing and revising the manuscript. CB performed virus infection, viral quantifications, and the optimization of the plaque assay for SARS-CoV-2 and prepared virus stock. SM performed virus isolation and the optimization of the plaque assay for SARS-CoV-2. NP performed analysis and prepared drug stock solutions. SB prepared cell lines and drug stock solutions. AT designed the study and edited the manuscript. PA 3, 4 reviewed and edited the manuscript. PA 1* designed and supervised the study, performed funding acquisitions, writing, and editing the manuscript. All authors read and approved the final manuscript. Declarations Ethics approval and consent to participate Not applicable. This work does not involve the use of human subjects and animals. All the procedures do not require IRB approval. Consent for publication Not applicable. This work does not contain data from any individual person. Competing interests The authors declare that they have no competing interests. • fast, convenient online submission • thorough peer review by experienced researchers in your field • rapid publication on acceptance • support for research data, including large and complex data types •..

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Mol ' 'Ther. 2021;29:873–85.', 'journal-title': 'Mol Ther'}], 'container-title': 'BMC Pharmacology and Toxicology', 'original-title': [], 'language': 'en', 'link': [ { 'URL': 'https://link.springer.com/content/pdf/10.1186/s40360-022-00580-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/article/10.1186/s40360-022-00580-8/fulltext.html', 'content-type': 'text/html', 'content-version': 'vor', 'intended-application': 'text-mining'}, { 'URL': 'https://link.springer.com/content/pdf/10.1186/s40360-022-00580-8.pdf', 'content-type': 'application/pdf', 'content-version': 'vor', 'intended-application': 'similarity-checking'}], 'deposited': { 'date-parts': [[2022, 6, 18]], 'date-time': '2022-06-18T09:12:48Z', 'timestamp': 1655543568000}, 'score': 1, 'resource': { 'primary': { 'URL': 'https://bmcpharmacoltoxicol.biomedcentral.com/articles/10.1186/s40360-022-00580-8'}}, 'subtitle': [], 'short-title': [], 'issued': {'date-parts': [[2022, 6, 18]]}, 'references-count': 61, 'journal-issue': {'issue': '1', 'published-print': {'date-parts': [[2022, 12]]}}, 'alternative-id': ['580'], 'URL': 'http://dx.doi.org/10.1186/s40360-022-00580-8', 'relation': {}, 'ISSN': ['2050-6511'], 'subject': ['Pharmacology (medical)', 'Pharmacology'], 'container-title-short': 'BMC Pharmacol Toxicol', 'published': {'date-parts': [[2022, 6, 18]]}, 'assertion': [ { 'value': '5 January 2022', 'order': 1, 'name': 'received', 'label': 'Received', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '9 June 2022', 'order': 2, 'name': 'accepted', 'label': 'Accepted', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, { 'value': '18 June 2022', 'order': 3, 'name': 'first_online', 'label': 'First Online', 'group': {'name': 'ArticleHistory', 'label': 'Article History'}}, {'order': 1, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Declarations'}}, { 'value': 'Not applicable. This work does not involve the use of human subjects and ' 'animals. All the procedures do not require IRB approval.', 'order': 2, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Ethics approval and consent to participate'}}, { 'value': 'Not applicable. This work does not contain data from any individual person.', 'order': 3, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Consent for publication'}}, { 'value': 'The authors declare that they have no competing interests.', 'order': 4, 'name': 'Ethics', 'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}], 'article-number': '41'}

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