Widely available lysosome targeting agents should be considered as potential therapy for COVID-19

Homolak, Jan; Kodvanj, Ivan

doi:10.1016/j.ijantimicag.2020.106044

Cited by 63 publications

(49 citation statements)

References 73 publications

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“…Azithromycin appears to act as a lysosomotropic agent, affecting lysosomal traffic and pH [ 13 , 14 ]. A similar mechanism has been proposed for the now controversial hydroxychloroquine [ 15 ], which alkalinizes phagolysosomes by inhibiting viral segmentation mediated by pH-dependent proteases, interfering with the fusion process and viral replication.…”

Section: Discussionmentioning

confidence: 99%

Antihistamines and azithromycin as a treatment for COVID-19 on primary health care – A retrospective observational study in elderly patients

Blanco

Bonilla

Homma

et al. 2021

Pulmonary Pharmacology & Therapeutics

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Section: Discussionmentioning

confidence: 99%

Antihistamines and azithromycin as a treatment for COVID-19 on primary health care – A retrospective observational study in elderly patients

Blanco

Bonilla

Homma

et al. 2021

Pulmonary Pharmacology & Therapeutics

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“…Endosomes and maturation of endosomes into a lysosome is featured by their acidic internal pH, which is required for acid proteases and critical for SARS-CoV-2 processing and internalization ( Wędrowska et al, 2020 ). The plasma and lysosomal membranes are highly permeable to the unionized form of weak bases but are essentially impervious to the protonated form of the bases ( Marceau et al, 2012 ; Homolak and Kodvanj, 2020 ). Accordingly, weak bases, unionized in the cytoplasm, can cross the lysosomal membrane and enter the lysosome.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Some drugs recognized as antiviral agents are lipophilic amines/weak bases that accumulate and preclude acidification of lysosomes, thus inhibiting virus internalization and post-internalization trafficking to the site of replication ( Sieczkarski and Whittaker, 2002 ; Kaufmann and Krise, 2007 ; Mercer et al, 2010 ). Such lysosomotropism is shared by some lipophilic amines and cationic amphiphilic drugs ( Kaufmann and Krise, 2007 ), including chloroquine and other anti-malarial drugs ( Homolak and Kodvanj, 2020 ). Indeed, lysosome targeting agents are considered a potential therapy for COVID-19 ( Homolak and Kodvanj, 2020 ).…”

Section: Mechanism Of Actionmentioning

confidence: 99%

“…Such lysosomotropism is shared by some lipophilic amines and cationic amphiphilic drugs ( Kaufmann and Krise, 2007 ), including chloroquine and other anti-malarial drugs ( Homolak and Kodvanj, 2020 ). Indeed, lysosome targeting agents are considered a potential therapy for COVID-19 ( Homolak and Kodvanj, 2020 ). However, the effectiveness of this mechanism of action to control viral infections is hampered by its low specificity, cell compensation mechanisms to lower/restore intralysosomal pH and egress entrapped amines from lysosomes ( Goldman et al, 2009 ), and the need for high drug dosage to allow substantial drug accumulation and alkalinization inside lysosomes, which also raises safety concerns.…”

Section: Mechanism Of Actionmentioning

confidence: 99%

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Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

Vela

2020

Front. Pharmacol.

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Outbreaks of emerging infections, such as COVID-19 pandemic especially, confront health professionals with the unique challenge of treating patients. With no time to discover new drugs, repurposing of approved drugs or in clinical development is likely the only solution. Replication of coronaviruses (CoVs) occurs in a modified membranous compartment derived from the endoplasmic reticulum (ER), causes host cell ER stress and activates pathways to facilitate adaptation of the host cell machinery to viral needs. Accordingly, modulation of ER remodeling and ER stress response might be pivotal in elucidating CoV-host interactions and provide a rationale for new therapeutic, host-based antiviral approaches. The sigma-1 receptor (Sig-1R) is a ligand-operated, ER membrane-bound chaperone that acts as an upstream modulator of ER stress and thus a candidate host protein for host-based repurposing approaches to treat COVID-19 patients. Sig-1R ligands are frequently identified in in vitro drug repurposing screens aiming to identify antiviral compounds against CoVs, including severe acute respiratory syndrome CoV-2 (SARS-CoV-2). Sig-1R regulates key mechanisms of the adaptive host cell stress response and takes part in early steps of viral replication. It is enriched in lipid rafts and detergent-resistant ER membranes, where it colocalizes with viral replicase proteins. Indeed, the non-structural SARS-CoV-2 protein Nsp6 interacts with Sig-1R. The activity of Sig-1R ligands against COVID-19 remains to be specifically assessed in clinical trials. This review provides a rationale for targeting Sig-1R as a host-based drug repurposing approach to treat COVID-19 patients. Evidence gained using Sig-1R ligands in unbiased in vitro antiviral drug screens and the potential mechanisms underlying the modulatory effect of Sig-1R on the host cell response are discussed. Targeting Sig-1R is not expected to reduce dramatically established viral replication, but it might interfere with early steps of virus-induced host cell reprogramming, aid to slow down the course of infection, prevent the aggravation of the disease and/or allow a time window to mature a protective immune response. Sig-1R-based medicines could provide benefit not only as early intervention, preventive but also as adjuvant therapy.

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“…9 Another avenue of potentially preventive or curative drugs is lysosome-targeted drugs, such as antibiotics, nonsteroidal antiinflammatories (NSAIDs), and proton pump inhibitors (PPIs). 10,11 In order to look for a treatment that could prevent the development of COVID-19 in elderly patients, we studied the treatments that elderly hospitalized patients were taking before they were tested for COVID-19.…”

Section: Introductionmentioning

confidence: 99%

Interest of Proton Pump Inhibitors in Reducing the Occurrence of COVID-19: A Case-Control Study

Blanc¹,

Waechter²,

Vogel³

et al. 2020

Preprint

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Background: COVID-19 is a disease of the elderly as 95% of deaths related to COVID-19 occur in people over 60 years of age. Despite the urgent need for a preventive treatment there are currently no serious leads, other than the vaccination. Objective: To find a preventive treatment of COVID-19 in elderly patients. Design: Retrospective case-control study. Setting: Robertsau Geriatric Hospital of the University Hospitals of Strasbourg, France. Patients: 179 elderly patients who had been in contact with the SARS-CoV-2, of whom 89 had tested RT-PCR-positive (COVID-pos) for the virus and 90 had tested RT-PCR-negative (COVID-neg). Measurements: Treatments within 15 days prior to RT-PCR (including antihypertensive drugs, antipsychotics, antibiotics, nonsteroidal anti-inflammatory drugs, proton pump inhibitors (PPIs), paracetamol, anticoagulant, oral antidiabetics (OADs), corticosteroids, immunosuppressants), comorbidities, symptoms, laboratory values, and clinical outcome were all collected using the electronic patient record. Results: COVID-pos patients more frequently had a history of diabetes (P=.016) and alcoholism (P=.023), a lower leukocyte count (P=.014) and a higher mortality rate– 29.2% versus 14.4% – (P=.014) when compared to COVID-neg patients. Patients on PPIs were 2.3 times less likely (odds ratio [OR] = 0.4381, 95% confidence interval [CI] [0.2331, 0.8175], P=.0053) to develop COVID-19 infection, compared to those not on PPIs. No other treatment decreased or increased this risk. COVID-19 patients on antipsychotics (P=.0013) and OADs (P=.0166) were less likely to die. Limitations: retrospective study. Conclusion: PPIs treatment lowered the risk of development of COVID-19 infection, and antipsychotics and OADs decreased the risk of mortality in geriatric patients. If further studies confirm this finding, PPIs could be used preventatively in the elderly in this pandemic context. Moreover, OADS and antipsychotics should be tested in clinical trials.

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Widely available lysosome targeting agents should be considered as potential therapy for COVID-19

Cited by 63 publications

References 73 publications

Antihistamines and azithromycin as a treatment for COVID-19 on primary health care – A retrospective observational study in elderly patients

Antihistamines and azithromycin as a treatment for COVID-19 on primary health care – A retrospective observational study in elderly patients

Repurposing Sigma-1 Receptor Ligands for COVID-19 Therapy?

Interest of Proton Pump Inhibitors in Reducing the Occurrence of COVID-19: A Case-Control Study

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