Drugs, Metabolites, and Lung Accumulating Small Lysosomotropic Molecules: Multiple Targeting Impedes SARS-CoV-2 Infection and Progress to COVID-19

Blaess, Markus; Kaiser, Lars; Sommerfeld, Oliver; Csuk, René; Deigner, Hans‐Peter

doi:10.3390/ijms22041797

Cited by 12 publications

(16 citation statements)

References 60 publications

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“…These could add to the action of these drugs in alleviating the pathophysiological consequences of SARS-CoV-2. Currently trials are on-going for several drug candidates (Blaess et al, 2021), including some with psychoactive substances like clomipramine (Nobile et al, 2021). However, more detailed clinical studies are required to validate their usefulness as potential drugs against viral infections including COVID-19 in large study populations.…”

Section: Antidepressant Drugs and Covid-19mentioning

confidence: 99%

Sphingolipids as Modulators of SARS-CoV-2 Infection

Törnquist

Asghar

Srinivasan

et al. 2021

Front. Cell Dev. Biol.

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of the COVID-19 pandemic with severe consequences for afflicted individuals and the society as a whole. The biology and infectivity of the virus has been intensively studied in order to gain a better understanding of the molecular basis of virus-host cell interactions during infection. It is known that SARS-CoV-2 binds to angiotensin-converting enzyme 2 (ACE2) via its spike protein. Priming of the virus by specific proteases leads to viral entry via endocytosis and to the subsequent steps in the life cycle of SARS-CoV-2. Sphingosine and ceramide belong to the sphingolipid family and are abundantly present in cell membranes. These lipids were recently shown to interfere with the uptake of virus particles of SARS-CoV-2 into epithelial cell lines and primary human nasal cells in culture. The mechanisms of action were partly different, as sphingosine blocked, whilst ceramide facilitated viral entry. Acid sphingomyelinase (ASM) is vital for the generation of ceramide and functional inhibition of ASM by drugs like amitriptyline reduced SARS-CoV-2 entry into the epithelial cells. Recent data indicates that serum level of sphingosine-1-phosphate (S1P) is a prognostic factor for COVID-2 severity. Further, stimulation of sphingosine-1-phosphate receptor 1 (S1PR1) might also constrain the hyper-inflammatory conditions linked to SARS-CoV-2. Here, we review recent exciting findings regarding sphingolipids in the uptake of SARS-CoV-2 and in the course of COVID-19 disease. More studies are required on the mechanisms of action and the potential use of antidepressant drugs and sphingolipid modifiers in SARS-CoV-2 infections and in the treatment of the more serious and fatal consequences of the disease.

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Section: Antidepressant Drugs and Covid-19mentioning

confidence: 99%

Sphingolipids as Modulators of SARS-CoV-2 Infection

Törnquist

Asghar

Srinivasan

et al. 2021

Front. Cell Dev. Biol.

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“…The author suggested that these compounds could be used off label using either local (inhalative) or systematic administration. Later, the author [ 11 ] developed the repurposing of lysosomotropic drugs (including numerous FIASMAs) in COVID-19 infection.…”

Section: Brief History Of the Studies Of Fiasmas In The Sars-cov-2 Infectionmentioning

confidence: 99%

“…The second point to be considered is the choice of the FIASMAs and the duration of their prescription within the study. Indeed, this latter parameter influences the accumulation in pulmonary tissue, and more specifically in lysosomes, to achieve the desired inhibition of acid sphingomyelinase [ 11 ]. The highest accumulation in plasma and also into the lysosome compartments (i.e., called steady-state) requires around 7 times the apparent elimination half-life of the drug to occur.…”

Section: Update (16 June 2021) On Studies With Fiasmas In the Sars-cov-2 Infectionmentioning

confidence: 99%

“…Hence, in order to estimate the potential effect of a drug on the course of COVID-19 infection in patients from retrospective studies, it would be necessary to make sure that the patients included in the study have previously been exposed to the drug(s) being studied at the time of inclusion, ideally by a chronic prescription. Given these pharmacokinetic features, in our previous paper [ 4 ] we have underlined that reaching a steady state to obtain a maximal effect would require a delay (seven times the half-life), and alternatively that a loading dose may be used to rapidly reach the steady state [ 11 ].…”

Section: Update (16 June 2021) On Studies With Fiasmas In the Sars-cov-2 Infectionmentioning

confidence: 99%

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Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

Loas

Corre

2021

Pharmaceuticals

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The SARS-CoV-2 outbreak is characterized by the need of the search for curative drugs for treatment. In this paper, we present an update of knowledge about the interest of the functional inhibitors of acid sphingomyelinase (FIASMAs) in SARS-CoV-2 infection. Forty-nine FIASMAs have been suggested in the treatment of SARS-CoV-2 infection using in silico, in vitro or in vivo studies. Further studies using large-sized, randomized and double-blinded controlled clinical trials are needed to evaluate FIASMAs in SARS-CoV-2 infection as off-label therapy.

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“…It contains two functional subunits: The S1 subunit binds to and interacts with the cell-surface receptors, while the S2 subunit mediates membrane fusion (2,3). Alongside S protein binding, cleavage of S proteins at the polybasic cleavage-sites by the membrane-associated Transmembrane Protease Serine 2 (TMPRSS2) and the lysosomal cysteine protease Cathepsin-L facilitates membrane-fusion and virus entry at the cellular endosomes (4,5). The released viral genomic RNA (gRNA), which carries a cap-structure and a polyA-tail, serves as a direct template for the cellular ribosomemediated translation of the two large ORFs: ORF1a and ORF1b.…”

Section: Sars-cov2 Replication Cyclementioning

confidence: 99%

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

et al. 2021

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Since November 2019 the SARS-CoV-2 pandemic has caused nearly 200 million infection and more than 4 million deaths globally (Updated information from the World Health Organization, as on 2nd Aug 2021). Within only one year into the pandemic, several vaccines were designed and reached approval for the immunization of the world population. The remarkable protective effects of the manufactured vaccines are demonstrated in countries with high vaccination rates, such as Israel and UK. However, limited production capacities, poor distribution infrastructures and political hesitations still hamper the availability of vaccines in many countries. In addition, due to the emergency of SARS-CoV-2 variants with immune escape properties towards the vaccines the global numbers of new infections as well as patients developing severe COVID-19, remains high. New studies reported that about 8% of infected individuals develop long term symptoms with strong personal restrictions on private as well as professional level, which contributes to the long socioeconomic problems caused by this pandemic. Until today, emergency use-approved treatment options for COVID-19 are limited to the antiviral Remdesivir, a nucleoside analogue targeting the viral polymerase, the glucocorticosteroide Dexamethasone as well as neutralizing antibodies. The therapeutic benefits of these treatments are under ongoing debate and clinical studies assessing the efficiency of these treatments are still underway. To identify new therapeutic treatments for COVID-19, now and by the post-pandemic era, diverse experimental approaches are under scientific evaluation in companies and scientific research teams all over the world. To accelerate clinical translation of promising candidates, repurposing approaches of known approved drugs are specifically fostered but also novel technologies are being developed and are under investigation. This review summarizes the recent developments from the lab bench as well as the clinical status of emerging therapeutic candidates and discusses possible therapeutic entry points for the treatment strategies with regard to the biology of SARS-CoV-2 and the clinical course of COVID-19.

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Drugs, Metabolites, and Lung Accumulating Small Lysosomotropic Molecules: Multiple Targeting Impedes SARS-CoV-2 Infection and Progress to COVID-19

Cited by 12 publications

References 60 publications

Sphingolipids as Modulators of SARS-CoV-2 Infection

Sphingolipids as Modulators of SARS-CoV-2 Infection

Update on Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) in SARS-CoV-2 Infection

Beyond Vaccines: Clinical Status of Prospective COVID-19 Therapeutics

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