Failed Repurposing of Lysosomotropic Drugs for COVID-19 Treatment or Prevention

François Marceau

doi:10.3390/ddc1010003

journal article Open Access Dec 02, 2022

Failed Repurposing of Lysosomotropic Drugs for COVID-19 Treatment or Prevention

François Marceau

Drugs and Drug Candidates Vol. 1 No. 1 pp. 22-28 · MDPI AG

View at Publisher Save 10.3390/ddc1010003

Abstract

The hope for the rapid discovery of an effective drug therapy for COVID-19 has led to several efforts to repurpose drugs approved for other indications. Lysosomotropic drugs, organic amines such as chloroquine, hydroxychloroquine, amiodarone and many others, were found to interfere with the viral life cycle in vitro but have failed in clinical trials. The properties of lysosomotropic drugs and the vacuolar cytopathology induced by them are briefly reviewed, including the critical role of lipophilicity, the central role of vacuolar (V)-ATPase for their concentration in acidic organelles, the altered function of these organelles including impaired endocytosis and secretion, macroautophagic accumulation and secondary phospholipidosis. The apparent preferential uptake of lysosomotropic drugs by phagocytic leukocytes (macrophages, neutrophils) and the high concentrations needed for a sustained disruption of vacuolar trafficking may have contributed to the failure of lysosomotropic drug repurposing for COVID-19.

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References

37

[1]

Kupferschmidt "Race to find COVID-19 treatments accelerates" Science (2020) 10.1126/science.367.6485.1412

[2]

Vanden Eynde, J.J. (2021). COVID-19: Failure of the DisCoVeRy Clinical Trial, and Now-New Hopes?. Pharmaceuticals, 14. 10.3390/ph14070664

[3]

Tummino "Drug-induced phospholipidosis confounds drug repurposing for SARS-CoV-2" Science (2021) 10.1126/science.abi4708

[4]

Salata "Antiviral activity of cationic amphiphilic drugs" Expert Rev. Anti Infect. Ther. (2017) 10.1080/14787210.2017.1305888

[5]

Sauvat "On-target versus off-target effects of drugs inhibiting the replication of SARS-CoV-2" Cell Death Dis. (2020) 10.1038/s41419-020-02842-x

[6]

Yang "Identification of SARS-CoV-2 entry inhibitors among already approved drugs" Acta Pharmacol. Sin. (2021) 10.1038/s41401-020-00556-6

[7]

Magagnoli "Outcomes of Hydroxychloroquine Usage in United States Veterans Hospitalized with COVID-19" Medcine (2020)

[8]

Ubals "BCN-PEP-CoV2 Research Group. A Cluster-Randomized Trial of Hydroxychloroquine for Prevention of COVID-19" N. Engl. J. Med. (2021) 10.1056/nejmoa2021801

[9]

Chakraborty "The Drug Repurposing for COVID-19 Clinical Trials Provide Very Effective Therapeutic Combinations: Lessons Learned From Major Clinical Studies" Front. Pharmacol. (2021) 10.3389/fphar.2021.704205

[10]

Navarese "Ion channel inhibition with amiodarone or verapamil in symptomatic hospitalized nonintensive-care COVID-19 patients: The ReCOVery-SIRIO randomized trial" Cardiol. J. (2022) 10.5603/cj.a2022.0072

[11]

Jha "Hydroxychloroquine plus personal protective equipment versus personal protective equipment alone for the prevention of laboratory-confirmed COVID-19 infections among healthcare workers: A multicentre, parallel-group randomised controlled trial from India" BMJ Open (2022)

[12]

Marceau "Cation trapping by cellular acidic compartments: Beyond the concept of lysosomotropic drugs" Toxicol. Appl. Pharmacol. (2012) 10.1016/j.taap.2011.12.004

[13]

Stadler "Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level" Am. J. Respir. Cell. Mol. Biol. (2008) 10.1165/rcmb.2007-0217oc

[14]

Morissette "Intracellular sequestration of amiodarone: Role of vacuolar ATPase and macroautophagic transition of the resulting vacuolar cytopathology" Br. J. Pharmacol. (2009) 10.1111/j.1476-5381.2009.00320.x

[15]

Parks "Lysosomotropic cationic drugs induce cytostatic and cytotoxic effects: Role of liposolubility and autophagic flux and antagonism by cholesterol ablation" Toxicol. Appl. Pharmacol. (2016) 10.1016/j.taap.2016.06.006

[16]

Parks "Autophagic flux inhibition and lysosomogenesis ensuing cellular capture and retention of the cationic drug quinacrine in murine models" PeerJ (2015) 10.7717/peerj.1314

[17]

Poole "Commentary. Lysosomotropic agents" Biochem. Pharmacol. (1974) 10.1016/0006-2952(74)90174-9

[18]

Moriyama "Membrane energization by proton pumps is important for compartmentalization of drugs and toxins: A new type of active transport" J. Exp. Biol. (1996) 10.1242/jeb.199.7.1447

[19]

Bawolak "Vacuolar ATPase-mediated sequestration of local anesthetics in swollen macroautophagosomes" Can. J. Anaesth. (2010) 10.1007/s12630-009-9220-9

[20]

Atilla "Effects of intracameral lidocaine on ocular tissues" Clin. Exp. Ophthalmol. (2003) 10.1046/j.1442-9071.2003.00604.x

[21]

Myers "Amiodarone lung: Pathologic findings in clinically toxic patients" Hum. Pathol. (1987) 10.1016/s0046-8177(87)80164-8

[22]

Ammoury "Photodistribution of blue-gray hyperpigmentation after amiodarone treatment: Molecular characterization of amiodarone in the skin" Arch. Dermatol. (2008) 10.1001/archdermatol.2007.25

[23]

Colby "Nodular amiodarone lung disease" Am. J. Surg. Pathol. (2008) 10.1097/pas.0b013e31816d1cbc

[24]

Bedrossian "Amiodarone pulmonary toxicity: Cytopathology, ultrastructure, and immunocytochemistry" Ann. Diagn. Pathol. (1997) 10.1016/s1092-9134(97)80008-1

[25]

Rodrigues "Emerging insights on the role of V-ATPase in human diseases: Therapeutic challenges and opportunities" Med. Res. Rev. (2021) 10.1002/med.21782

[26]

Dow "Molecular genetic analysis of V-ATPase functions in Drosophila melanogaster" J. Exp. Biol. (1997) 10.1242/jeb.200.2.237

[27]

Inoue "Targeted disruption of the gene encoding the proteolipid subunit of mouse vacuolar H+-ATPase leads to early embryonic lethality" Biochim. Biophys. Acta (1999) 10.1016/s0005-2728(99)00096-1

[28]

Morissette "Intense pseudotransport of a cationic drug mediated by vacuolar ATPase: Procainamide-induced autophagic cell vacuolization" Toxicol. Appl. Pharmacol. (2008) 10.1016/j.taap.2007.12.031

[29]

Marceau "Vacuolar ATPase-mediated cellular concentration and retention of quinacrine: A model for the distribution of lipophilic cationic drugs to autophagic vacuoles" Drug Metab. Dispos. (2009) 10.1124/dmd.109.028480

[30]

Roy "High affinity capture and concentration of quinacrine in polymormonuclear neutrophils via vacuolar ATPase-mediated ion trapping: Comparison with other peripheral blood leukocytes and implications for the distribution of cationic drugs" Tox. Appl. Pharmacol. (2013) 10.1016/j.taap.2013.04.004

[31]

Reasor "Drug-induced phospholipidosis: Issues and future directions" Expert Opin. Drug Saf. (2006) 10.1517/14740338.5.4.567

[32]

Piccoli "Amiodarone impairs trafficking through late endosomes inducing a Niemann-Pick C-like phenotype" Biochem. Pharmacol. (2011) 10.1016/j.bcp.2011.07.090

[33]

Kuzu "Effect of lysosomotropic molecules on cellular homeostasis" Pharmacol. Res. (2017) 10.1016/j.phrs.2016.12.021

[34]

Coronavirus biology and replication: implications for SARS-CoV-2

Philip V’kovski, Annika Kratzel, Silvio Steiner et al.

Nature Reviews Microbiology 2021 10.1038/s41579-020-00468-6

[35]

Ghosh "β-Coronaviruses Use Lysosomes for Egress Instead of the Biosynthetic Secretory Pathway" Cell (2020) 10.1016/j.cell.2020.10.039

[36]

Warhurst "Hydroxychloroquine is much less active than chloroquine against chloroquine-resistant Plasmodium falciparum, in agreement with its physicochemical properties" J. Antimicrob. Chemother. (2003) 10.1093/jac/dkg319

[37]

Durcan "Immunomodulators in SLE: Clinical evidence and immunologic actions" J. Autoimmun. (2016) 10.1016/j.jaut.2016.06.010

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Details

Published: Dec 02, 2022
Vol/Issue: 1(1)
Pages: 22-28
License: View

Authors

F

François Marceau

Axe Microbiologie-Infectiologie et Immunologie, Research Center, CHU de Québec-Université Laval, Québec, QC G1V 4G2, Canada

Funding

Natural Sciences and Engineering Research Council of Canada Award: MOP-74448

Canadian Institutes of Health Research Award: MOP-74448

Cite This Article

François Marceau (2022). Failed Repurposing of Lysosomotropic Drugs for COVID-19 Treatment or Prevention. Drugs and Drug Candidates, 1(1), 22-28. https://doi.org/10.3390/ddc1010003

Failed Repurposing of Lysosomotropic Drugs for COVID-19 Treatment or Prevention

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