key: cord-0780654-zfov86kg authors: Le Corre, Pascal; Loas, Gwenolé title: Repurposing functional inhibitors of acid sphingomyelinase (fiasmas): an opportunity against SARS‐CoV‐2 infection? date: 2021-03-01 journal: J Clin Pharm Ther DOI: 10.1111/jcpt.13390 sha: 813d2024cbd4055799320a9488cf20c9a2f35f97 doc_id: 780654 cord_uid: zfov86kg WHAT IS KNOWN AND OBJECTIVE: Infection by SARS‐CoV‐2, the virus responsible of COVID‐19, is associated with limited treatment options. The purpose of this study was to evaluate the rationale for repurposing functional inhibitors of acid sphingomyelinase (FIASMAs), several of which are approved medicines, for the treatment of SAR‐CoV‐2 infections. COMMENT: We propose and discuss the FIASMAs’ lysosomotropism as a possible explanation for their observed in vitro activities against viruses, and more specifically against infections caused by coronaviruses such as SARS‐CoV‐2. Successful in vitro‐to‐in vivo translation of FIASMAs requires that their pharmacokinetics (dosing regimen and drug‐drug interactions) are matched with viral kinetics. WHAT IS NEW AND CONCLUSION: Drug repurposing to ensure rapid patient access to effective treatment has garnered much attention in this era of the COVID‐19 pandemic. The observed lysosomotropic activity of small‐molecule FIASMA compounds suggests that their repurposing as potential drugs against SARS‐CoV‐2 is promising. The SARS-CoV-2 outbreak poses major therapeutic problems, and there is an urgent need for a specific antiviral agent to treat this infection, thus decreasing viral shedding and subsequent transmis- Numerous organic molecules, including currently marketed drugs, have the potential to functionally inhibit, in a reversible and additive manner, the activity of acid sphingomyelinase (ASM) which is a lysosomal glycoprotein involved in a wide range of disorders (4) including virus infections. These molecules identified by the acronym FIASMA (ie functional inhibitors of acid sphingomyelinase) have the potential to disrupt the entry of viruses into cells. The purpose of this study was to provide a rationale for repurposing of FIASMAs (functional inhibitors of ASM) for the prophylactic and/ or therapeutic treatment of SARS-CoV-2 infections through a literature search in PubMed and the medRxiv.org preprint server for Health Sciences. However, residual ASM activity is necessary for cell viability. There are significant differences in the intra-lysosomal capture speed depending on lipophilicity (logP) and degree of ionization In general, viruses exploit the cellular mechanisms of endocytosis to penetrate the cytosol. However, several different mechanisms of internalization may be involved, including clathrin-mediated endocytosis, macropinocytosis, caveolar/lipid raft-mediated endocytosis, or one of several incompletely characterized clathrin-independent and caveolin/lipid raft-independent mechanisms.(9) During infection with Coronoviridae, lipid raft-mediated endocytosis (10) and the clathrin-mediated pathway (11) have both been demonstrated to play a role in internalization, resulting in the identification of these processes as potential targets for drugs acting at the internalization step (ie fusion and entry). However, the targeting of the late compartments of the endocytic pathway after the delivery of the SARS-CoV genome to the cytoplasm is also a viable approach for the disruption of replication, as shown with the FIASMA amiodar- In almost all studies, the status of the FIASMAs was not known by the authors. In the first set of studies, (11, 12, (14) (15) (16) (17) (18) the antiviral activity of FIASMAs against the SARS-CoV and MERS-CoV viruses was explored. In the second set of studies, different drugs were tested against the SARS-CoV-2 using in silico (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) and in vitro studies. (30) (31) (32) (33) (34) (35) (36) (37) (38) (39) (40) These are listed in Table 1 In total, 32 FIASMAs have been identified through in silico, in vitro or in vivo studies as potential antiviral drug candidates against SARS-CoV, MERS-CoV or SARS-CoV-2. Of these, six show activity against all three coronaviruses (chlorpromazine, clomipramine, emetine, fluphenazine, loperamide and promethazine, see Table 1 ). Considering the results of recent in vivo studies, four FIASMAs Left: ASM is anchored to the inner leaflet of the lysosomal membrane by electrostatic forces so that the enzyme is protected from proteolytic degradation. Specific stimuli allow the translocation of ASM from the inner lysosome to the external leaflet of the cell where ASM catalyses the hydrolysis of sphingomyelin into ceramide and phosphorylcholine. Sphingomyelin is the most abundant sphingolipid component of the mammalian plasma membrane where it is associated with cholesterol to form lipid rafts. Right: FIASMA are cationic drugs with lipophilic properties that diffuse in the lysosome by passive diffusion and potentially via an additional mechanism using ABCB1 transporter located on the lysosomal membrane. These drugs become protonated in the intra-lysosomal acidic environment and increase the intra-lysosomal pH so that ASM is detached from the inner leaflet of the lysosomal membrane and is further degraded by proteolysis. ASM translocation is no longer effective and the formation of lipid rafts is altered. Hence, different mechanisms of internalization used by viruses (ie fusion and entry) to penetrate in the cytosol of cells are altered. However, reaching a steady state to obtain a maximal effect would require a delay (approximately seven-times the half-life) that may prove unsuitable in an epidemic context, either for prevention or for curative use. Alternatively, a loading dose may be used to reach the steady state more rapidly, provided the tolerance profile is not a limiting factor. Furthermore, as illustrated for these two prototypic drugs, oral bioavailability is a factor of inter-individual variability that needs to be considered. Other variability factors that may impact dosing, including renal and hepatic impairment and drug-drug interactions with concomitant medications, should also be considered especially because these drug candidates are lipophilic drugs usually with significant first-pass effect. In particular, attention should be paid to FIASMAs interacting with P-gp, either as substrate and/or as inhibitor (Table 1) . P-gp is present in the lysosomal membrane (51) FIASMAs should be tested in vitro to explore their activity against SARS-CoV-2. Fourth, FIASMAs with either a protective effect in the general population or a significant activity in vitro should be tested in vivo using a notably randomized double-blinded study against a placebo. The drug repurposing approach has garnered significant attention in the COVID-19 pandemic era, providing some hope of an effective treatment in the near future. Current knowledge suggests that All the authors (PLC and GL) disclose any financial and personal relationships with other people or organizations that could inappropriately influence their work. All authors performed the literature search and wrote the manuscript. Pascal Le Corre https://orcid.org/0000-0003-4483-0957 Gwenolé Loas https://orcid.org/0000-0003-1719-916X A trial of lopinavir-ritonavir in adults hospitalized with severe covid-19 Covid-19.the search for effective therapy Drug repurposing: progress, challenges and recommendations Inhibition of acid sphingomyelinase by tricyclic antidepressants and analogons Functional Inhibitors of Acid Sphingomyelinase (FIASMAs): a novel pharmacological group of drugs with broad clinical applications Identification of new functional inhibitors of acid sphingomyelinase using a structure-property-activity relation model Functional Inhibitors of Acid Sphingomyelinase (FIASMAs) Melatonin acts as an antidepressant by inhibition of the Acid Sphingomyelinase/Ceramide system Virus entry by endocytosis Murine coronavirus requires lipid rafts for virus entry and cell-cell fusion but not for virus release Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted Amiodarone alters late endosomes and inhibits SARS coronavirus infection at a post-endosomal level Updated approaches against SARS-CoV-2 Old drugs as lead compounds for a new disease? Binding analysis of SARS coronavirus main proteinase with HIV, psychotic and parasite drugs Is the anti-psychotic, 10-(3-(dimethylamino)propyl)phenothiazine (promazine), a potential drug with which to treat SARS infections? Lack of efficacy of promazine on SARS-CoV replication in a mouse model Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection Screening of an FDA-approved compound library identifies four small-molecule inhibitors of Middle East respiratory syndrome coronavirus replication in cell culture Testing of Middle East respiratory syndrome coronavirus replication inhibitors for the ability to block viral entry A SARS-CoV-2 protein interaction map reveals targets for drug repurposing In Silico discovery of candidate drugs against Covid-19 Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2 An investigation into the identification of potential inhibitors of SARS-CoV-2 main protease using molecular docking study Artificial intelligence approach fighting COVID-19 with repurposing drugs Potential inhibitors against papain-like protease of novel coronavirus (SARS-CoV-2) from FDA approved drugs. ChemRxiv Morphological cell profiling of SARS-CoV-2 infection identifies drug repurposing candidates for COVID-19. version 2. bioRxiv Drug Repurposing for Candidate SARS-CoV-2 Main Protease Inhibitors by a Novel In Silico Method Old drugs for newly emerging viral disease Savitz S Drug repurposing for COVID-19 using graph neural network with genetic, mechanistic, and epidemiological validation On-target versus offtarget effects of drugs inhibiting the replication of SARS-CoV-2 Identification of antiviral drug candidates against SARS-CoV-2 from FDA-approved drugs Remdesivir, lopinavir, emetine, and homoharringtonine inhibit SARS-CoV-2 replication in vitro Potential antiviral options against SARS-CoV-2 infection Repurposing old drugs as antiviral agents for coronaviruses FDA approved drugs with broad anti-coronaviral activity inhibit SARS-CoV-2 in vitro Targeting the SARS-CoV-2 Main Protease to Repurpose Drugs for COVID-19 The serotonin reuptake inhibitor Fluoxetine inhibits SARS-CoV-2 FDA approved calcium channel blockers inhibit SARS-CoV-2 infectivity in epithelial lung cells Jiao T Identification of potent and safe antiviral therapeutic candidates against SARS-CoV-2 Calcium channel blocker amlodipine besylate is associated with reduced case fatality rate of COVID-19 patients with hypertension Targeting the endolysosomal host-SARS-CoV-2 interface by clinically licensed functional inhibitors of acid sphingomyelinase (FIASMA) including the antidepressant fluoxetine Pharmacological inhibition of acid sphingomyelinase prevents uptake of SARS-CoV-2 by epithelial cells Towards a pharmacochemical hypothesis of the prophylaxis of SARS-CoV-2 by psychoactive substances Prevention of COVID-19 by drug repurposing: rationale from drugs prescribed for mental disorders Association between SSRI Antidepressant Use and reduced risk of intubation or death in hospitalized patients with coronavirus disease 2019: a multicenter retrospective observational study Nifedipine and Amlodipine are associated with improved mortality and decreased risk for intubation and mechanical ventilation in elderly patients hospitalized for COVID-19 Fluvoxamine vs Placebo and clinical deterioration in outpatients with symptomatic COVID-19: a randomized clinical trial Understanding SARS-CoV-2 endocytosis for COVID-19 drug repurposing Amitriptyline disposition in young and elderly normal men Pharmacokinetics of chlorpromazine and key metabolites P-glycoprotein mediates drug resistance via a novel mechanism involving lysosomal sequestration Intracellular ABCB1 as a Possible Mechanism to Explain the Synergistic Effect of Hydroxychloroquine-Azithromycin Combination in COVID-19 Therapy Dosing will be a key success factor in repurposing antivirals for COVID-19 Repurposing functional inhibitors of acid sphingomyelinase (fiasmas): an opportunity against SARS-CoV-2 infection?