USE OF PSYCHOTROPIC DRUGS FOR THE TREATMENT OF CORONAVIRUS INFECTIONS

Abstract

The coronavirus SARS-Cov-2 which started in Wuhan, China, in December 2019 induced a threat to global health. Patients with mental disorders were thought to be at increased risk of becoming infected for several reasons but very much to the inventors' surprise, these psychiatric units remained nearly empty during the lock-down period as if psychiatric patients were protected from SARS-Cov-2 infection. Thus the inventors mined the literature to identify approved drugs with in vitro antiviral activities with a special emphasis on psychotropic drugs and compared these molecules using chemoinformatics strategies to the drugs most commonly used in their psychiatric department. A large number of compounds were found to be cationic amphiphilic drugs (CADs) and as such tend to also be phospholipidosis inducers in vitro (PLD). Several molecules most commonly used in their department were also found to have in vitro antiviral activity and/or can be clustered with compounds with known in vitro antiviral activity. Thus, drugs most commonly used for mental disorders with known in vitro antiviral activities are often CADs. In silico and in vitro analyses of these compounds together with the observations made in the department strongly suggest that commonly used psychotropic drugs and some related anti-histamine agents used as anxiolytics should protect psychiatric patients from SARS-Cov-2 infection.

Claims

1. A method of treating a coronavirus infection in a subject in need thereof comprising administering to the patient a therapeutically effective amount of at least one drug selected from the group consisting of Desloratadine, Promethazine, Loratadine, Azelastine, Pizotifen, Bromodiphenhydramine, Diphenhydramine, Cyproheptadine, Oxomemazine, Cetirizine, Hydroxyzine, Alimemazine, Amisulpride, Aripiprazole, Citalopram, Clozapine, Cyamemazine, Diazepam, Escitalopram, Lorazepam, Melatonin, Quetiapine, Sertraline, Valproate, Zopiclone, Rupatadine, Azatadine, Promazine, Profenamine, Methdilazine, Perazine, Perphenazine, Ketotifen, Orphenadrine and Lithium.

2. The method of claim 1 wherein the at least one drug is selected from the group consisting of Desloratadine, Promethazine, Loratadine and Azelastine.

3. The method of claim 1 wherein the at least one drug is selected from the group consisting of Desloratadine, Promethazine and Loratadine.

4. The method of claim 1 wherein the at least one drug is selected from the group consisting of Desloratadine and Loratadine.

5. The method of claim 1 wherein the at least one drug is Desloratadine.

6. The method of claim 1 wherein at least two drugs are administered to the patient.

7. The method of claim 1 wherein the at least one drug is administered to the subject in combination with at least one other therapeutic agent;

8. The method of claim 1 wherein the at least one drug is administered in combination with at least one antibody.

9. The method of claim 8 wherein the at least one antibody is bamlanivimab, casirivimab, cilgavimab, regdanvimab, sotrovimab, tixagevimab, etesevimab, imdevimab, tocilizumab, COR101, MR17, SR4, COV2-2064, VHH-72, TY-027 or JMB2002.

10. The method of claim 1 wherein the at least one drug is administered in combination with at least one vaccine.

11. The method of claim 10 wherein the at least one vaccine is mRNA-1273, BNT162b2, AZD1222, CVnCoV vaccine, NVX-CoV2373, BBIBP-CorV, Ad26.COV2.S, Ad5-nCov, Gam-COVID-Vac, CoVLP, BBV152-COVAXIN, AG0302-COVID19, SCB-2019, QazCovid-in, UB-612 or EpiVacCorona.

12. The method of claim 1 wherein the at least one drug is administered to the subject in combination with Azithromycin.

13. The method of claim 1 wherein the at least one drug is administered to the subject in combination with at least one drug selected from the group consisting of Chloroquine, Hydroxyl-chloroquine, Nicotine, Clemastine, Cloperastine, and Haloperidol.

14. The method of claim 7, wherein the at least one other therapeutic agent is at least one other antiviral agent.

15. The method of claim 14, wherein the at least one other antiviral agent is selected from the group consisting of remdesivir, lopinavir, and ritonavir.

Description

FIGURES

[0028] FIG. 1: Cytopathic effect (i.e. structural changes in a host cell resulting from a viral infection) measured as a function of concentrations of Desloratadine (A), Azelastine (B) or Promethazine (C).

EXAMPLE 1

[0029] Methods

[0030] To explore psychotropic drugs and rationalize putative molecular mechanisms, we first identified the most commonly used drugs in hospital settings and treatments massively used in private practice (i.e., consumption of all the drugs in the Psychiatric department of Henri Mondor Hospital, Creteil, France). We ended up with 18 drugs reported in Table 1. Moreover, we selected ten other drugs used in different therapeutic areas with known in vitro antiviral activities through literature mining (see also recent reviews)..sup.9, 10 In these previous studies, in vitro drug repurposing strategies have been carried out on viruses such as HIV, MERS, SARS, and/or Ebola among others..sup.11, 12 Yet one recently reported repurposing studies has been performed on SARS-CoV-2..sup.13 These ten molecules are presented in the bottom part of Table 1. Chemoinformatics strategies were applied to compare these ten drugs with known antiviral activities with the 18 molecules most commonly used in our department. These involved calculation of molecular descriptors (pKa, log P, fingerprints) and then clustering compounds by chemical similarity.

[0031] We observed that all ten reference compounds (e.g., chlorpromazine, promethazine, chloroquine, clomifene) with in vitro antiviral activities belong to a wide group of chemicals commonly referred to as cationic amphiphilic drugs or CADs. These molecules are characterized by hydrophobic-aromatic ring systems and a side chain that carries one (or more) ionizable amine functional group. To define the CAD of the selected compounds, we used computed pKa and log P values as reported in..sup.14 We considered cationic compounds as molecules with an amine group (the most basic group was selected) with a basic pKa value>7.1, which indicates that these substances are mainly protonated a low pH values (i.e. in the endosomal-lysosomal system, pH values are in the range of 6.5 to about 4.5). Computation of pKa values were carried out with the ChemAxon chemistry toolkit (https://chemaxon.com/).

[0032] Amphiphilic compounds have both hydrophilic and hydrophobic chemical moieties in their structures and this global property can be estimated by log P values (i.e., an estimation of the lipophilic character of small drug-like compounds). DataWarrior was used to compute log P values..sup.15 CADs often induce phospholipidosis (drug-induced phospholipidosis or PLD) in vitro..sup.16 Hundreds of drugs have been tested in vitro to assess if they induce phospholipidosis..sup.14, 17 When experimental data are not available, the property can also be predicted..sup.17, 18

[0033] Compounds were also grouped into families using similarity measures computed via the statistical package R and the ChemMine chemical toolkit and the implemented hierarchical clustering method was used..sup.19 Similarity analyses were also performed with the 2D-Rubber Band Scaling approach applied to different similarity criterion..sup.15

[0034] Chemoinformatics clustering analysis was also carried out over a collection of 4642 approved drugs. The clustering was performed by combining structural similarities found by the MACCS fingerprints or the count for the presence of specific organic functions or the consensus between MACCS fingerprints and the organic function count. A total of 3040 clusters were first identified. Then, focusing in the appropriate areas of the chemical space (i.e., compounds predicted to be CAD) and similar with the drugs mentioned in Table 1 allowed for the selection of 17 other molecules (Table 2).

[0035] Results:

[0036] Ten reference drugs (anti-malarial and anti-histamine agents and psychotropic drugs) with known antiviral activities were selected (Table 1). Independently of their exact chemical structures (not shown), the first observation is that they are all CADs. They are also known or predicted PLD compounds. For the 18 most commonly prescribed psychotropic drugs (Table 1), we note that, if we set aside lithium which is of different nature as not an organic molecule, among the remaining 17 molecules, 14 are also CADs and/or PLD.

[0037] There are different possibilities to group compounds in families. We clustered compounds by comparing chemical substructures and the presence of functional chemical groups. Two clusters with five or more members were identified. Interestingly, this approach groups compounds with known in vitro antiviral activities such as Chlorphenoxamine with commonly prescribed drugs such as Escitalopram. Similarly, Promethazine that is known to have in vitro antiviral activities (Table 1) is clustered with commonly prescribed drugs such as Cyamemazine or Alimemazine while the more structural diverse and commonly prescribed Aripiprazole compound can also be considered to belong to this family of molecules. Antimalarial compounds, Chloroquine and Hydroxychloroquine, form a small cluster but are also closely related to Clomifene, a molecule used to treat fertility disorders (i.e., all these compounds are neighbors in the 2D space).

[0038] The other approved drugs that cluster with the compounds most commonly given to psychiatric patients are reported Table 2. These molecules have therefore the potential to act on Covid-19 according to our chemoinformatics analysis.

[0039] Discussion:

[0040] Drugs against SARS-CoV-2 could operate at different stages of the virus lifecycle. To protect the population, acting on the virus entry phase through drug repurposing is an attractive solution. Different strategies can be envisioned, from specific inhibition of some proteases and receptors, to more fundamental mechanisms involving endocytosis or both. We present below our analysis on psychotropic drugs and some related molecules and suggest that many of these drugs impede virus entry and/or intracellular trafficking.

[0041] While not fully understood, the SARS-CoV-2 lifecycle comprises several steps: cell attachment and cell entry and intracellular trafficking, viral uncoating, nucleotide replication and viral assembly, and final release of viral genetic material in the cytoplasm..sup.8 A critical event for entering the cells involves the binding of the SARS-CoV-2 spike glycoprotein RBD domain to the angiotensin converting enzyme 2 (ACE2) receptor..sup.20 Subsequently the virus enters the endosomes and eventually fuse viral and lysosomal membranes. To fuse membranes, the spike protein needs to be proteolytically activated (i.e., cleaved with associated conformational changes) by the transmembrane surface serine protease TMPRSS2 or other proteases and endosomal/lysosomal cathepsins while furin preactivation assists SARS-CoV-2 entry in some types of cells..sup.8, 20-22 The SARS-CoV-2 virus entry and intracellular trafficking therefore appear to involve the endosomal (clathrin-dependent or not)/lysosomal pathway and complex autophagy processes suggesting that targeting endocytosis could be of potential therapeutic interest..sup.23, 24

[0042] The ten selected drugs used as reference compounds with known in vitro antiviral activities are reported in Table 1. These compounds are CADs, characterized by hydrophobic-aromatic ring systems and an overall hydrophobic side chain that carries one (or more) ionizable amine functional group..sup.9 CADs can be partially charged at physiological pH but are protonated in the more acidic endolysosomal compartments. When protonated, the drugs are trapped in lysosomes and can severely perturb cell functions and trafficking. Related with these observations, it is known that many CADs induce phospholipidosis (drug-induced phospholipidosis or PLD), a situation characterized by the accumulation of phospholipids within the lysosome resulting from several mechanisms such as direct binding of the drugs to the membranes and/or inhibition of enzymes, raise of the pH value of the endolysosomal compartments toward neutrality . . . )..sup.16 Among the ten reference compounds, eight are also psychotropic drugs and/or anti-histamine agents that have known in vitro antiviral activity (Table 1). According to our calculation, these molecules are all CADs. They are also known or predicted PLD compounds. Further, it we take the example of a compound from another therapeutic class such as Chloroquine, this anti-malarial compound is a CAD and a PLD compound. It is a lysosomotropic agent that accumulates in acidic organelles such as endosomes and lysosomes and neutralizes their pH thereby inhibiting protease activities with subsequent altered cleavages of the spike proteins damaging some events required for virus entry and possibly affecting the function of ACE2 (not shown).sup.25. Another molecule like Chlorpromazine is a CAD and PLD agent and is known to inhibit clathrin-medicated endocytosis (not shown)..sup.26 If we compare the chemical structure (global structure or the presence of chemical substructures) and physico-chemical properties (Table 1) of these ten reference compounds with known in vitro antiviral activity with the 18 most commonly prescribed psychiatric medications (Table 1), we note that among these, if we set aside lithium, 14 are CADs and/or PLD and several of these molecules can be clustered and/or share many common chemical substructures (i.e., they are chemically related and many should follow the well-established similarity property principle which states that similar compounds have similar biological properties). In this context, it seems reasonable to speculate that many commonly used psychiatric drugs protect patients from SARS-CoV-2 via perturbation of the endo-lysosomal pathway with potential impairments of autophagy processes.

[0043] In parallel, we also searched for evidences that these 18 most commonly used psychotropic drugs in our department could have known in vitro antiviral activities, even if the mechanisms are not known and even if not specifically documented for SARS-CoV-2. Among these 18 molecules, at least ten have documented antiviral activities (Table 1). For some viruses such as Ebola, it has even been shown that drug combination could be beneficial..sup.27 The combination of for instance Toremifene (a CAD drug and predicted PLD by comparison with the highly similar compound tamoxifen, a known PLD agent) used in the treatment of advanced breast cancer with the anti-depressant Sertraline molecule (a CAD agent and PLD compound) can be used as an example. We propose that combining psychotropic drugs that have low adverse drug reaction properties with anti-histamine drugs and/or Nicotine could be of interest for the prevention of SARS-CoV-2 infection. Of importance, Tomerifen was initially proposed to possess anti-Ebola activities through destabilization of the Ebola GP glycoprotein, essential for virus entry into the cells (i.e., like the spike protein of SARS-CoV-2), but more recent investigations suggest that this drug acts because it is a CAD compound that impairs various endolysosomal functions and proteins..sup.28

[0044] Our analysis suggests that psychotropic drugs (including some anti-histamine agents used as anxiolytics) could, in association or not with nicotine, protect the population from SARS-CoV-2 during the virus entry phase and intracellular trafficking essentially by interfering with the endolysosomal pathway and further interactions with some specific receptors. Chemically, these compounds tend to all be cationic amphiphilic drugs and/or in vitro phospholipidosis inducers. Further experimental assessments need to be performed but chemical and clinical evidences strongly suggest that a preventive treatment is at hand by repurposing the reported psychotropic drugs against SARS-CoV-2 infection.

[0045] Starting from the two lists of molecules found by clinical observations and via chemoinformatics strategies (Table 1 and Table 2), we then text-mined drug repository databases in search for secondary effects, doses commonly prescribed and the mode of administration. Second, we further investigated the chemistry of the compounds via computational analysis looking for the presence of toxicophores (i.e., chemical structures that can lead to adverse drug reactions in some population). Based upon this analysis, we propose a top priority list of molecules that should have very limited secondary effects in the general population for clinical trials consisting of Desloratadine, Promethazine, Azelastine and Loratadine.

[0046] The second priority list of molecules include: Pizotifen, Bromodiphenhydramine, Diphenhydramine, Cyproheptadine, Oxomemazine, Cetirizine, and Hydroxyzine.

[0047] The third priority list of drugs involve: Alimemazine, Amisulpride, Aripiprazole, Citalopram, Clozapine, Cyamemazine, Diazepam, Escitalopram, Lorazepam, Melatonin, Quetiapine, Sertraline, Valproate, Zopiclone, Rupatadine, Azatadine, Promazine, Profenamine, Methdilazine, Perazine, Perphenazine, Ketotifen and Orphenadrine.

[0048] As mentioned above, these molecules could be combined or administrated with, for instance, Nicotine or antiviral agents or antibodies or vaccines.

[0049] To illustrate the efficiency of our invention, we tested in vitro three molecules from our top priority list (Loratadine was not tested as it needs to be metabolized, in the human body, to its main active form, Desloratadine).

EXAMPLE 2

[0050] Virus Strain Used for the Assays

[0051] SARS-CoV-2 clinical isolates D614G (GenBank accession number MW322968) was isolated from a SARS-CoV-2 RT-PCR confirmed patients by inoculating Vero cells with sputum sample or nasopharyngeal swabs in our biosafety level-3 (BSL-3) facility. Viral stock were generated using one passage of isolate on Vero cells. Titration of viral stock was performed on Vero E6 by the limiting dilution assay allowing calculation of tissue culture infective dose 50% (TCID50).

[0052] Evaluation of Antiviral Activities of the Drugs

[0053] One day prior to the assay, Vero-E6 cells (ATCC® CRL-1586) were plated in a 96-wells flat bottom tissue culture treated plate at a density of 2×10.sup.4 cells/well. On the day of the assay, Vero-E6 cells were pre-treated with the different concentration (i.e. 10 μM, 5 μM and 2 μM) of the indicated drugs diluted in Dulbecco's Modified Eagles Medium (DMEM). After 1 h, the cells were infected with 50 μl of a viral inoculum at 1×10.sup.3 TCID50/ml and incubated for 2 h at 37° C. to allow infection. Then, the virus-drug mixture was removed, cells were rinsed 3 times with PBS and were further cultured with fresh drug-containing medium (DMEM 5% FBS) for 3 days until microscopic examination was performed. Cytotoxicity of the tested drugs were determined in the same experiment in mock infected cells. The half maximal inhibitory concentration (IC.sub.50) were analyzed by non-linear regression using a four-parameter dosage-response variable slope model with the GraphPad Prism 8.0.2 software (GraphPad Software, USA).

[0054] The results are shown in FIG. 1 and Table 3, highlighting the antiviral activity of Desloratadine (FIG. 1A), Azelastine (FIG. 1B) and Promethazine (FIG. 1C). These results demonstrate the efficiency of psychotropic and structurally related antihistaminic drugs for the treatment of coronavirus infections. These molecules were not found to be cytotoxic.

[0055] Conclusion:

[0056] These results are concomitants with other experiments. In Hou et al. (Chemico-Biological Interactions 338 (2021) 109420), the antiviral effect of Loratadine and Desloratadine was tested. These two molecules were efficient to block spike protein-ACE2 interaction, thus inhibiting SARS-CoV-2 entry to cells. No cytotoxicity was observed under 20 μM concentrations.

[0057] Here, we demonstrated the antiviral effects of psychotropic and structurally related antihistaminic drugs against SARS-CoV-2 infection and propose some already approved drugs that could be repositioned for the treatment against COVID-19.

[0058] Tables:

TABLE-US-00001 TABLE 1 Main psychotropic drugs and reference compounds used to develop our rationale. Number of Name basic N/pKa PLD Examples of (rank of use in of the most (experimental published in vitro our hospital) Class cLogP basic group CAD or predicted) antiviral activity 18 main psychotropic drugs used in our department Alimemazine (15) anxiolytic 4.2 1/9.42 y y (predicted) not known Amisulpride (>15) anti- 0.9 1/7.05 n y not known psychotic Aripiprazole (8) anti- 4.4 1/7.46 y y Drug combination psychotic for Ebola virus (J Infect Dis 2018; 218(suppl_5): S672-S8) Cetirizine (15) anti- 2.1 1/7.42 y n (predicted) HRV (Antiviral histamine Res 2009; 81(3): anxiolytic 226-33.; PLoS One 2017; 12(7): e0165415) Citalopram (>15) anti- 2.8 1/9.78 y y HIV depressant (J Neuroimmune Pharmacol 2007; 2(1): 120-7) Clozapine (2) anti- 3.2 1/7.35 y y Inhibition of psychotic Epstein-Barr Virus Lytic Reactivation HIV (Viruses 2019; 11(5); Schizophr Res 1997; 25(1): 63-70.) Cyamemazine (10) anti- 4.0 1/9.42 y y (predicted) not known psychotic Diazepam (7) anti- 2.9 0/2.92 n n not known depressant Escitalopram (>15) anti- 2.7 1/9.78 y y (predicted) not known depressant Hydroxyzine (>15) anti- 3.0 1/7.77 y y Selective inhibition histamine of hepatitis C virus anti- infection (Antimicrob depressant Agents Chemother 2014; 58(6): 3451-60) Lithium (4) mood- NA 0/−4.2 n n Antiviral effect of stabilizing lithium chloride on mammalian orthoreoviruses (Microb Pathog 2016; 93: 152-7) Lorazepam (3) anxiolytic 2.9 0/−2.2 n n not known Melatonin (9) anti- 1.5 0 n y Possible roles depressant in bacterial and viral infections (Recent Pat Endocr Metab Immune Drug Discov 2012; 6(1): 30-9) Nicotine (1) 1.2 1/8.6  partial y (predicted) Inhibits the production of pro- inflammatory cytokines in mice infected with cox- sackievirus B3 (Life Sci 2016; 148: 9-16) Quetiapine(11) anti- 2.7 1/7.06 y y not known psychotic Sertraline (>15) anti- 4.2 1/9.85 y y Ebola virus depressant Zika Virus HIV in vivo (J Neuroimmune Pharmacol 2007; 2(1): 120-7; Sci Transl Med 2015; 7(290): 290ra89; Cell Host Microbe 2016; 20(2): 259-70) Valproate (5) anti- 2.2 0/NA  n n HSV (Virus Res depressant 2016; 214: 71-9) Zopiclone (6) sedative  0.71 1/6.89 n y (predicted) not known 10 reference compounds with known in vitro antiviral activity used for comparison with the above molecules Chloroquine (NA) anti- 4.0  2/10.32 y y MERS, SARS, malarial Filovirus (Sci Transl Med 2015; 7(290): 290ra89) Chlorphenoxamine anti- 3.4 1/8.87 y y (predicted) MERS, SARS (>15) histamine (Antimicrob Agents Chemother 2014; 58(8): 4885-93) Chlorpromazine anti- 4.6 1/9.2  y y MERS, SARS (>15) psychotic (Antimicrob Agents anti Chemother 2014; histamine 58(8): 4885-93) Clemastine (>15) anti- 4.6 1/9.55 y y SARS-CoV-2 histamine (Nature. 2020 July; 583(7816): 459-468) Clomifene (NA) women 5.1 1/9.31 y y Ebola, HCV infertility (Microbes Infect 2013; 15(1): 45-55; Sci Transl Med 2013; 5(190): 190ra79) Clomipramine (>15) anti- 4.5 1/9.2  y y MERS, SARS depressant (Antimicrob Agents Chemother 2014; 58(8): 4885-93) Cloperastine (>15) anti- 4.6 1/8.82 y y SARS-CoV-2 histamine (Nature. 2020 July; 583(7816): 459-468) Haloperidol (>15) anti- 4.3 1/8.05 y y SARS-CoV-2 psychotic (Nature. 2020 July; 583(7816): 459-468) Hydroxyl- anti- 3.1 2/9.76 y y SARS-Cov-2 chloroquine (NA) malarial (Nature. 2020 July; 583(7816): 459-468) Promethazine (>15) anti- 3.9 1/9.05 y y Ebola (Sci Transl Med histamine 2015; 7(290): 290ra89)

[0059] The first part of the table lists the main 18 drugs used in our department and/or in private practice. The second part represents a list of ten molecules with known in vitro antiviral activity that were used for comparison with our compounds. It turned out that several of these ten reference molecules are also used in our hospital setting and/or in private practice. Further, mining of the literature indicated that several molecules commonly used in our department also have in vitro antiviral activities. This information was thus added to the table.

[0060] We searched for some common properties that could be shared by these compounds and more specifically, we initially tried to answer two questions: are these molecules cationic amphiphilic drugs (CADs)? and could they be inducers of phospholipidosis, at least in vitro (PLD)?. The scientific rationale is that several CADs have in vitro antiviral activity (e.g., Chloroquine, Hydroxychloroquine, Chlorpromazine, Promethazine, Sertraline or Clomifen) and that CADs tend to also be PLD..sup.16, 19 This type of molecules could possibly impede virus entry into the host cells due to the intrinsic properties of CADs. These molecules should also impair the endolysosomal pathway and intracellular trafficking and can bind or regulate some specific receptors and enzymes directly or indirectly (e.g., directly inhibit some enzymes, bind to the membrane and/or impede the function of some phospholipases or change the pH and perturb the functioning of some proteases).

[0061] CAD molecules usually have a hydrophobic ring structure and a side chain with a cationic amine group (weak base, usually a primary, secondary or tertiary nitrogen atom N bound to a carbon C of an alkyl chain). CADs are in general not fully ionized at a physiologic pH and have an overall hydrophobicity that can be monitored using computed log P values. The amine group (N) of these compounds becomes permanently protonated in acidic compartments (e.g., endosomes or lysosomes). The drugs are then trapped and concentrated, inducing membrane structure perturbation and in some cases compromising cell viability. We defined cationic compounds as molecule with a basic pKa value above >7.1, which indicates that these substances are mainly protonated a low pH values..sup.14 Indeed, in the endosomal-lysosomal system, the pH values are in the range of 6.5 to about 4.5. Amphiphilic compounds have, by definition, both hydrophilic and hydrophobic chemical moieties in their structures. A computed log P in the range of 2-3 to 9 combined with the presence of a positively charged N group provide an approximate definition of the amphiphilic character of a small drug-like compound. Using this reasoning, nicotine could partially fit the definition of CAD.

[0062] The log P values (c Log P) (logarithm of the octanol/water partition coefficient water/octanol system, estimation of lipophilicity, high values indicate hydrophobic molecules while low values suggest that the molecule is hydrophilic) were computed with DataWarrior using the unionized (neutral) form of the molecule as input..sup.15 pKa values to estimate the protonation state of the most basic group were computed with the ChemAxon chemistry toolkit (https://chemaxon.com/). The number of basic nitrogen(s) was estimated at physiological pH and at pH=6 (i.e., as in the endosome). Numerous compounds should be protonated at pH=6 and indeed chloroquine and hydroxychloroquine are known to have two charged amine groups at this pH. At pH=7.4 however, many of these compounds should still be partially positively charged. Hundreds of molecules are known to induce phospholipidosis in vitro. We gathered this information from the literature..sup.14, 16, 17 When the experimental data were missing, the property was predicted with our FAF-Drugs4 web server..sup.18 In the table, “y” means Yes and “n” means No.

TABLE-US-00002 TABLE 2 Additional drugs with predicted antiviral activities identified by clustering molecules commonly given to the psychiatric patients in our Department (Table 1) with 4642 other approved drugs. The metrics used to evaluate chemical similarity involved the merging of a circular fingerprint algorithm with a 3D-pharmacophore approach. Visualization of the molecules to select the compounds involved the use of T-distributed Stochastic Neighbor Embedding and the creation of 2D similarity network maps. 17 extra molecules were identified and considered relevant for the treatment and/or prevention of Covid-19. These compounds are highly similar to the molecules used in the Henri Mondor psychiatric department. Also, these 17 extra molecules belong to the CAD (cationic amphiphilic drugs) category but Loratadine. This compound is not expected to carry a positive charge at pH = 7, but will carry a positive charge after metabolism in the human body. For instance, Desloratadine, the active metabolite of Loratadine, is predicted to display such positive charge. Class CAD Loratadine antihistamine Partial, becomes CAD after metabolism in the human body Desloratadine antihistamine Yes Rupatadine antihistamine Yes Azatadine antihistamine Yes Oxomemazine antihistamine Yes Promazine antipsychotic Yes Profenamine antihistamine Yes Methdilazine antihistamine Yes Perazine antipsychotic Yes Perphenazine antipsychotic Yes Pizotifen antihistamine Yes Ketotifen antihistamine Yes Cyproheptadine antihistamine Yes Diphenhydramine antihistamine Yes Orphenadrine antihistamine Yes Bromodiphenhydramine antihistamine Yes Azelastine antihistamine Yes

TABLE-US-00003 TABLE 3 Half-maximal inhibitory concentrations (i.e. IC50) of Desloratadine, Azelastine or Promethazine. IC50 (μM) Desloratadine 5.75 Azelastine 5.75 Promethazine 9.22

REFERENCES

[0063] Throughout this application, various references describe the state of the art to which this invention pertains. The disclosures of these references are hereby incorporated by reference into the present disclosure. [0064] 1. Farha M A, Brown E D. Drug repurposing for antimicrobial discovery. Nat Microbiol 2019; 4(4): 565-77. [0065] 2. Grimsey E M, Piddock L J V. Do phenothiazines possess antimicrobial and efflux inhibitory properties? FEMS Microbiol Rev 2019; 43(6): 577-90. [0066] 3. Yao Q, Wang P, Wang X, et al. Retrospective study of risk factors for severe SARS-Cov-2 infections in hospitalized adult patients. Pol Arch Intern Med 2020. [0067] 4. Vieta E, Perez V, Arango C. Psychiatry in the aftermath of COVID-19. Rev Psiquiatr Salud Ment 2020. [0068] 5. Li H J, Gao D S, Li Y T, Wang Y S, Liu H Y, Zhao J. Antiviral effect of lithium chloride on porcine epidemic diarrhea virus in vitro. Res Vet Sci 2018; 118: 288-94. [0069] 6. Melander R J, Melander C. The Challenge of Overcoming Antibiotic Resistance: An Adjuvant Approach? ACS Infect Dis 2017; 3(8): 559-63. [0070] 7. Bilinska K, Jakubowska P, C S VONB, Butowt R. Expression of the SARS-CoV-2 Entry Proteins, ACE2 and TMPRSS2, in Cells of the Olfactory Epithelium: Identification of Cell Types and Trends with Age. ACS Chem Neurosci 2020. [0071] 8. Shang J, Wan Y, Luo C, et al. Cell entry mechanisms of SARS-CoV-2. Proc Natl Acad Sci USA 2020. [0072] 9. Salata C, Calistri A, Parolin C, Baritussio A, Palu G. Antiviral activity of cationic amphiphilic drugs. Expert Rev Anti Infect Ther 2017; 15(5): 483-92. [0073] 10. Ekins S, Mottin M, Ramos P, et al. Deja vu: Stimulating open drug discovery for SARS-CoV-2. Drug Discov Today 2020. [0074] 11. Johansen L M, DeWald L E, Shoemaker C J, et al. A screen of approved drugs and molecular probes identifies therapeutics with anti-Ebola virus activity. Sci Transl Med 2015; 7(290): 290ra89. [0075] 12. Dyall J, Coleman C M, Hart B J, et al. Repurposing of clinically developed drugs for treatment of Middle East respiratory syndrome coronavirus infection. Antimicrob Agents Chemother 2014; 58(8): 4885-93. [0076] 13. Gordon D E, Jang G M, Bouhaddou M, et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020. [0077] 14. Muehlbacher M, Tripal P, Roas F, Kornhuber J. Identification of drugs inducing phospholipidosis by novel in vitro data. Chem Med Chem 2012; 7(11): 1925-34. [0078] 15. Sander T, Freyss J, von Korff M, Rufener C. DataWarrior: an open-source program for chemistry aware data visualization and analysis. J Chem Inf Model 2015; 55(2): 460-73. [0079] 16. Breiden B, Sandhoff K. Emerging mechanisms of drug-induced phospholipidosis. Biol Chem 2019; 401(1): 31-46. [0080] 17. Przybylak K R, Alzahrani A R, Cronin M T. How does the quality of phospholipidosis data influence the predictivity of structural alerts? J Chem Inf Model 2014; 54(8): 2224-32. [0081] 18. Lagorce D, Bouslama L, Becot J, Miteva M A, Villoutreix B O. FAF-Drugs4: free ADME-tox filtering computations for chemical biology and early stages drug discovery. Bioinformatics 2017; 33(22): 3658-60. [0082] 19. Cao Y, Charisi A, Cheng L C, Jiang T, Girke T. ChemmineR: a compound mining framework for R. Bioinformatics 2008; 24(15): 1733-4. [0083] 20. Hoffmann M, Kleine-Weber H, Schroeder S, et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell 2020; 181(2): 271-80 e8. [0084] 21. Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020; 5(4): 562-9. [0085] 22. Ou X, Liu Y, Lei X, et al. Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV. Nat Commun 2020; 11(1): 1620. [0086] 23. Millet J K, Whittaker G R. Physiological and molecular triggers for SARS-CoV membrane fusion and entry into host cells. Virology 2018; 517: 3-8. [0087] 24. Yang N, Shen H M. Targeting the Endocytic Pathway and Autophagy Process as a Novel Therapeutic Strategy in COVID-19. Int J Biol Sci 2020; 16(10): 1724-31. [0088] 25. Wang H, Yang P, Liu K, et al. SARS coronavirus entry into host cells through a novel clathrin- and caveolae-independent endocytic pathway. Cell Res 2008; 18(2): 290-301. [0089] 26. Inoue Y, Tanaka N, Tanaka Y, et al. Clathrin-dependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted. J Virol 2007; 81(16): 8722-9. [0090] 27. Dyall J, Nelson E A, DeWald L E, et al. Identification of Combinations of Approved Drugs With Synergistic Activity Against Ebola Virus in Cell Cultures. J Infect Dis 2018; 218(suppl_5): S672-S8. [0091] 28. Fan H, Du X, Zhang J, et al. Selective inhibition of Ebola entry with selective estrogen receptor modulators by disrupting the endolysosomal calcium. Sci Rep 2017; 7: 41226.