Introduction
Structure of Sphingomyelinase
Sphingolipid Metabolism
Sphingolipid Transport and Uptake
Role of Sphingolipids in Viral Entry
Drug | Mechanism | References |
---|---|---|
Propofol | The propofol has a role for caveolae (specifically caveolin-1) in propofol-induced bronchodilatation. Due to its lipid nature, propofol may transiently disrupt caveolar regulation, thus altering ASM [Ca2+] and decreasing caveolin-1 expression | [57] |
Isoflurane | The isoflurane increases membrane fluidity and the permeability of the blood–brain barrier by distributing the highly ordered lipid domains with saturated lipids. It also weakened the sterol-phospholipid association in cholesterol-rich membranes | |
Pentobarbital | Pentobarbitals modify the physical characteristics of lipid rafts on model membranes and cause lipid membrane disorder of brain plasma membranes | [60] |
Lidocaine | Lidocaine is observed to distribute the erythrocyte membrane lipid rafts reversibly and abolish flotillin-1 in lipid rafts together with depleting cholesterol. In addition, the Lidocaine hydrochloride, an amphipathic local anaesthetic, is shown to reversibly disrupt rafts in erythrocyte membranes and alter the Gsα dependent signal transduction pathway. These findings provide evidence of rafts' presence while maintaining normal cholesterol content in erythrocyte membranes and confirm a role for raft-associated Gsα in signal transduction in erythrocytes | |
Tetracaine | Tetracaine induces lipid chain mobility, destabilizes the supported lipid bilayers, and induces lipid raft distribution and solubilization. Tetracaine causes a curvature change in the bilayer, which leads to the formation of the subsequent formation of up to 20-μm-long flexible lipid tubules as well as the formation of micron-size holes | [63] |
Dibucaine | Dibucaine hydrochloride has a distribution effect on lipid rafts. The inserting Dibucaine molecules into lipid bilayers induces a reduction in the ternary liposome's miscibility transition temperature (Tc) and a reduction in the phase boundary line tension. This suggests that the Dibucaine.HCl molecules may disturb ion channel functions by affecting the lipid bilayers surrounding the ion channels | [64] |
Bupivacaine | Bupivacaine stereostructure specifically interacts with membranes containing cholesterol, which is consistent with the clinical features of S (-)-bupivacaine. The bupivacaine interacted with liposomal membranes to increase membrane fluidity. They also revealed that the interactivity with lipid bilayer membranes is largely consistent with the local anaesthetic potency | [65] |
Dexmedetomidine Levomedetomidine Clonidine | Dexmedetomidine and clonidine acted on lipid bilayers to increase the membrane fluidity with potencies varying by a compositional difference of membrane lipids. Dexmedetomidine showed greater interactivity with neuro-mimetic and cardiomyocyte-mimetic membranes than clonidine, consistent with their comparative lipophilicity and activity. The effects of α2-adrenergic agonists on lipid raft model membranes were much weaker than those on other membranes, indicating that lipid rafts are not mechanistically relevant to them. Higher interactive dexmedetomidine was discriminated from lower interactive levomedetomidine in the presence of chiral cholesterol in membranes. An interactivity difference between the two enantiomers was largest in the superficial region of lipid bilayers, and the rank order of their membrane-interacting potency was reversed by replacing cholesterol with epicholesterol, suggesting that cholesterol’s 3β-hydroxyl groups positioned close to the membrane surface are responsible for the enantioselective interaction | [66] |
Morphine | Morphine increases the membrane fluidity of membranes | [67] |
Aspirin | It is observed that aspirin increases membrane fluidity, disrupts the membrane organization, and prevents raft formation | [64] |
Indomethacin Naproxen Ibuprofen | These compounds affected the organization of rat-like ordered lipid and protein membrane nanoclusters | [68] |
Edelfosine | It is observed that Edelfosine increases the fluidity of lipid rafts. Edelfosine is associated with cholesterol and colocalizes in vivo with rafts, causing the raft's structure modification | [69] |
Perifosine | It is observed that perifosine causes disrupted membrane raft domains | [70] |
Edelfosine Miltefosine | The edelfosine and miltefosine increase the fluidity of raft model membranes | [71] |
Erucylphosphocholine | Erucylphosphocholine is observed to increase the membrane raft fluidity and weaken the interaction between cholesterol and sphingomyelin | [72] |
2-Hydroxyoleic acid | 2-Hydroxyoleic acid increases the membrane raft fluidity | [73] |
Cisplatin | Cisplatin increases the membrane fluidity and induces apoptosis, which was inhibited by cholesterol (30 μg/mL) and monosialoganglioside-1 (80 μM) | |
Azithromycin | Azithromycin is observed to increase the fluidity of raft-like membranes | [76] |
Daunorubicin | Daunorubicin is observed to affect lipid rafts by decreasing the fluidity of raft-like membranes | [77] |
Doxorubicin | Doxorubicin is an anticancer drug that increases the fluidity of binary membranes but not ternary membranes | [78] |
Quercetin | Quercetin is observed to suppress the accumulation of lipid rafts to inhibit TNF-α production. In addition, it increases the fluidity of raft model membranes in mouse macrophages | |
Luteolin | Luteolin suppresses the accumulation of lipid rafts to inhibit TNF-α production in mouse macrophages | [80] |
EGCG | Epigallocatechin gallate (EGGG) decreases the fluidity of binary membranes. On the other hand, it induces lipid raft clustering and apoptotic cell death in human multiple myeloma cells | [81] |
Dimeric procyanidin | Dimeric procyanidin increases the membrane fluidity in human acute T-cell leukemia cells | [82] |
Hexameric procyanidin | Hexameric procyanidin decreases the membrane fluidity and prevents the lipid raft disruption induced by deoxycholate in human colon cancer cells | [83] |
Emodin | Emodin causes disrupted lipid rafts in human umbilical vein endothelial cells | [84] |
Ginsenosides | Ginsenosides increase the membrane fluidity and reduce the raft-marker protein concentration in lipid rafts in HeLa cells | [85] |
Saikosaponin | Saikosaponin inhibits Lipopolysaccharide-induced cytokine expression and Toll-like receptor localization in lipid rafts, and reduces membrane cholesterol levels in mouse macrophages | [86] |
Methyl-beta-cyclodextrin (MβCD) treatment | It is observed that MβCD causes depletion of cholesterol in the rafts by methyl-beta-cyclodextrin (MβCD) treatment impaired the expression of the cell surface receptor angiotensin-converting enzyme 2 (ACE2), resulting in a significant increase in SARS-CoV-2 entry into cells | [87] |
Statins | Statins reduces cholesterol synthesis by inhibiting the activity of HMG-CoA reductase. Statins could modulate virus entry, acting on the SARS‐CoV‐2 receptors, ACE2 and CD147, and/or lipid rafts engagement. In addition, statins, by inducing autophagy activation, could regulate virus replication or degradation, exerting protective effects | [88] |
The Acid Sphingomyelinase/Ceramide System in Viruses
Trafficking Process utilized in viral entry
Clathrin and dynamin-independent pathways utilized in viral entry
SARS-CoV-2 Entry by Lipid Rafts
Lipid Raft Distribution Reduces SARS-CoV-2 Infectivity
No | FIASMAs | FDA | Molecular weight g/mole | References |
---|---|---|---|---|
1 | Alverine | Not approved | 281.44 | |
2 | Astemizole | Approved | 458.571 | [127] |
3 | Aprindine | Not approved | 322.487 | |
4 | Amlodipine | Approved | 408.879 | |
5 | Ambroxol | Approved | 378.1028 | [125] |
6 | Amiodarone | Approved | 645.31 | |
7 | Amitriptyline | Approved | 277.403 | |
8 | Benztropin | Approved | 307.429 | |
9 | Bepridil | Approved | 366.54 | |
10 | Biperidene | Approved | 311.46 | |
11 | Camylofine | Approved | 320.47 | [127] |
12 | Carvedilol | Approved | 406.474 | |
13 | Cepharanthine | Not approved | 606.7 | |
14 | Clofazimine | Approved | 473.4 | |
15 | Clemastine | Approved | 343.89 | |
16 | Cloperastine | Approved | 329.86 | |
17 | Chlorprothixene | Not approved | 315.86 | |
18 | Chlorpromazine | Approved | 318.86 | |
19 | Clofazimine | Approved | 473.39 | |
20 | Clomiphene | Approved | 405.966 | |
21 | Clomipramine | Approved | 314.9 | |
22 | Conessine | Not approved | 356.6 | |
23 | Cyclobenzaprine | Approved | 275.4 | |
24 | Cyproheptadine | Approved | 287.39 | |
25 | Desipramine | Approved | 266.388 | |
26 | Desloratadine | Approved | 310.82 | |
27 | Dicycloverine | Approved | 309.487 | |
28 | Dilazep | Approved | 604.7 | |
29 | Dimebon | Not approved | 319.452 | |
30 | Doxepine | Approved | 279.376 | |
31 | Drofenine | Approved | 317.47 | |
32 | Emetine | Not approved | 480.639 | |
33 | Fendeline | Approved | 315.5 | [127] |
34 | Flupenthixol | Not approved | 434.5219 | |
35 | Fluoxetine | Approved | 309.33 | |
36 | Fluvoxamine | Approved | 318.335 | |
37 | Fluphenazine | Approved | 437.523 | |
38 | Flupentixol | Not approved | 434.5219 | |
39 | Flunarizine | Not approved | 404.495 | |
40 | Hydroxyzin | Approved | 374.904 | |
41 | Imipramine | Approved | 280.407 | |
42 | Loperamide | Approved | 477.037 | |
43 | Loratadine | Approved | 382.88 | |
44 | Maproteline | Approved | 277.403 | |
45 | Melatonine | Not approved | 232.278 | |
46 | Mebhydroline | Not approved | 276.376 | [125] |
47 | Mebeverine | Not approved | 429.55 | |
48 | Mibefradile | Not approved | 495.63 | |
49 | Norfluoxetine | Approved | 295.30 | [127] |
50 | Nortriptyline | Approved | 263.377 | |
51 | Paroxetine | Approved | 329.37 | |
52 | Perphenazine | Approved | 403.97 | |
53 | Pimozide | Approved | 461.56 | |
54 | Pimethexene | Approved | 293.434 | [127] |
55 | Profenamine | Discontinued | 312.5 | |
56 | Promethazine | Approved | 284.4191 | |
57 | Promazine | Not approved | 284.42 | [127] |
58 | Protriptyline | Approved | 263.377 | |
59 | Quinacrine | Not approved | 400.0 | |
60 | Sertindole | Not approved | 440.941 | |
61 | Solasodine | Not approved | 413.64 | |
62 | Sertraline | Approved | 306.229 | |
63 | Suloctidil | Not approved | 337.6 | [127] |
64 | Tamoxifene | Approved | 371.515 | |
65 | Thioridazine | Approved | 370.6 | |
66 | Tomatidine | Not approved | 415.7 | |
67 | Terfenadine | Not approved | 471.673 | [127] |
68 | Trifluoperazine | Approved | 407.497 | |
69 | Triflupromazine | Approved | 352.4 | |
70 | Trimipramine | Approved | 294.434 | |
71 | Zolantidine | Not approved | 381.5 |
Functional Inhibitors of Acid Sphingomyelinase FIASMAs’ Mechanism of Action
In Vitro Docking of Potent Antiviral Compounds Based on Sphingolipid Inhibition
Compound | Docking score (S) (kcal/mol) | Hot spots involved in binding |
---|---|---|
APPA (Co-crystalized ligand) | − 28.75 | Asn316, His280, and Zn(II) ions |
Amiodarone (Drug candidate) | − 10.43 | Tyr572 |
Alverine | − 8.22 | Ile 487 |
Astemizole | − 10.81 | Asn488 and His457 |
Aprindine | − 8.41 | Asn488 and Thr456 |
Amlodipine | − 9.14 | Zn(II) ions |
Ambroxol | − 8.54 | His455, His457, Glu386, and Zn(II) ions |
Amitriptyline | − 7.94 | Ile 487 |
Benztropine | − 8.18 | ––––- |
Bepridil | − 10.47 | Asn488 |
Biperidene | − 7.96 | Thr456 |
Camylofine | − 8.55 | His280 and His455 |
Carvedilol | − 11.28 | ––––- |
Cepharanthine | − 11.06 | Asn316, His280, Ile487, and His457 |
Clofazimine | − 10.37 | Ile 487 |
Clemastine | − 8.40 | ––––- |
Cloperastine | − 8.04 | ––––- |
Chlorprothixene | − 7.86 | Asn323, His280, and Phe486 |
Chlorpromazine | − 8.29 | Ile 487 |
Clomiphene | − 8.95 | ––––- |
Clomipramine | − 8.31 | His280 |
Conessine | − 8.33 | ––––- |
Cyclobenzaprine | − 8.03 | Asn488 and His457 |
Cyproheptadine | − 8.45 | ––––- |
Desipramine | − 8.38 | Asn316 and Glu386 |
Desloratadine | − 8.77 | Asn323 and His280 |
Dicycloverine | − 7.53 | His280 and His457 |
Dilazep | − 12.58 | His457 |
Dimebon | − 9.41 | Asn488 |
Doxepine | − 8.36 | Asn488 |
Drofenine | − 8.08 | Asn316 and His317 |
Emetine | − 11.65 | ––––- |
Fendeline | − 9.06 | Ile487 |
Flupenthixol | − 10.39 | His455, His280, His457, Ile487, and Zn(II) ions |
Fluoxetine | − 10.09 | His457, Ile487, and Lys103 |
Fluvoxamine | − 9.37 | His455, Ile487, and Zn(II) ion |
Fluphenazine | − 9.59 | His455, His317, and Glu386 |
Flunarizine | − 9.20 | His317 |
Hydroxyzine | − 10.96 | His455, Ile487, and Zn(II) ions |
Imipramine | − 7.76 | Asn488 |
Loperamide | − 10.13 | Asn316, His280, and Lys103 |
Loratadine | − 8.47 | ––––- |
Maproteline | − 7.96 | His280, Thr456, and His457 |
Melatonine | − 9.23 | His280 |
Mebhydroline | − 8.02 | Asn488 |
Mebeverine | − 11.14 | His457 |
Mibefradil | − 10.09 | Asn488 and Glu386 |
Norfluoxetine | − 10.34 | His280 and Zn(II) ions |
Nortriptyline | − 7.49 | His457 |
Paroxetine | − 10.23 | Asn488 |
Perphenazine | − 9.78 | His455, His317, and Zn(II) ions |
Pimozide | − 11.29 | His280, His317, and Asn488 |
Profenamine | − 7.72 | His317 |
Promethazine | − 7.62 | Ile487 |
Promazine | − 8.09 | Ile487 |
Protriptyline | − 8.48 | Ile487 |
Quinacrine | − 10.19 | His280 |
Sertindole | − 10.55 | His457 |
Solasodine | − 8.64 | His317 |
Sertraline | − 7.77 | His317 |
Suloctidil | − 8.64 | His455 |
Tamoxifene | − 8.56 | Phe486 |
Thioridazine | − 8.00 | His317 |
Tomatidine | − 8.85 | His280 |
Terfenadine | − 10.39 | His455 and His457 |
Trifluoperazine | − 10.22 | Ile487 |
Triflupromazine | − 8.72 | Asn488 |
Trimipramine | − 7.79 | His280, Asn323, and Phe486 |
Zolantidine | − 9.13 | His457 and Ile487 |
FIASMAs | In silico study | In vitro study | In vivo study | Refences |
---|---|---|---|---|
Alverine | - | Show functional inhibition of ASMase with residual ASM activity of 21.7 | - | [27] |
Astemizole | Astemizole formed one hydrogen bond with ACE2 while three hydrogen bonds with H1R. Nitrogen on the hexahydropyridine ring of astemizole forms hydrogen bonds with ARG393 of ACE2 with distances of 2.14 Å. Asmidazole forms hydrogen bonds with LYS1016, ANS1055, and ASN1053 of H1R with distances of 1.92 Å, 2.39 Å, and 1.91 Å, respectively | The results showed that astemizole can bind to the ACE2 receptor and inhibit the invasion of SARS-COV-2 Spike pseudoviruses | – | [170] |
Aprindine | - | Show functional inhibition of ASMase with residual ASM activity of 27.5 | – | [27] |
Amlodipine | Amlodipine showed binding affinity to S glycoprotein and 3-chymotrypsin-like protease was − 5.5, − 6.0, and − 5.2, respectively | Amlodipine Besylate showed antiviral activity against OC43 cells through binding and acting as a carbonic anhydrase inhibitor, calcium channel inhibitor, and PDE inhibitor | Chronic treatment with amlodipine could be significantly associated with low mortality of COVID-19 in patients | |
Ambroxol | ––- | –––– | The system of sphingomyelinase/ceramide is very significant in transmitting SARS-CoV-2. They used Ambroxol, which has trans-4-[(2,4-dibromanilin-6-yl)-methyamino]-cyclohexanol structure as an inhibitor of ASMase. The Ambroxol is applied by inhalation, suggesting that the drug might inhibit the acid sphingomyelinase and, thereby, infection with SARS-CoV-2. They used vesicular stomatitis virus pseudoviral particles presenting SARS-CoV-2 spike protein on their surface (pp-VSV-SARS-CoV-2 spike), a bona fide system for mimicking SARS-CoV-2 entry into cells. They found that entry of pp-VSV-SARS-CoV-2 spike required activation of acid sphingomyelinase and release of ceramide, all of which were prevented by pretreatment with ambroxol. They also obtained nasal epithelial cells from human volunteers before and after inhalation of ambroxol. Inhalation of ambroxol reduced acid sphingomyelinase activity in nasal epithelial cells and prevented pp-VSV-SARS-CoV-2 spike-induced acid sphingomyelinase activation, ceramide release, and entry of pp-VSV-SARS-CoV-2 spike ex vivo [123] | [123] |
Amiodarone | – | Amiodarone reduced SARS-CoV-2 and IAV titres ≥ 90% without any cytotoxic effects. It also inhibited SARS2 replication, reducing supernatant viral RNA load with a promising activity level | Amiodarone administration in an early disease phase might block SARS-CoV-2 replication | |
Amitriptyline | Amitriptyline showed binding to the allosteric site of SARS-CoV-2 Main Protease with − 5.9 kcal/mol | The results showed that the increased ASMase activity and ceramide release were inhibited by pretreatment with Amitriptyline at 0.625, 1.25, 2.5, and 5 μM. Thus, amitriptyline was regarded as an active inhibitor of ASMase | In healthy volunteers, oral administration of amitriptyline blocked infection of freshly isolated nasal epithelial cells with SARS‐CoV‐2 | |
Benztropin | - | Benztropin inhibited ASMase activity by at least 50% at 10 µM | In healthy volunteers, oral administration of amitriptyline blocked infection of freshly isolated nasal epithelial cells with SARS‐CoV‐2 | |
Bepridil | Amitriptyline showed binding to the allosteric site of SARS-CoV-2 Main Protease with − 5.1 kcal/mol | Bepridil possesses significant anti − SARS-CoV-2 activity in both Vero E6 and A459/ACE2 cells in a dose-dependent manner with low micromolar effective concentration 50% (EC50) values | - | [178] |
Biperidene | - | Showed inhibitory impact on ASMase | - | [174] |
Camylofine | - | Camylofin showed an inhibitory impact with a pKa of 10.02 | - | [127] |
Carvedilol | - | - | Carvedilol usage was not significantly associated with a reduced likelihood of a positive laboratory test result for SARS-CoV-2 among the 5 subgroups after adjusting for age, sex, race, smoking, and various disease comorbidities | [130] |
Cepharanthine | Cepharanthine can block both the NSP12‐NSP7 interface and the NSP12‐NSP8 interface of SARS‐CoV‐2 and the NSP12‐NSP8 interface of SARS‐CoV.2 | Cepharanthine showed potential antiviral activities against SARS-CoV-2, with IC50 values between 0.1 and 10 μM | [179] | |
Clofazimine | Clofazimine inhibit 3CLPRO | Clofazimine showed IC50 value of 0.01 µM | Our data provide evidence that clofazimine may have a role in controlling the current COVID-19 pandemic and, more importantly, in dealing with coronavirus diseases that may emerge | |
Clemastine | Clemastin inhibits SARS-CoV-2 replication by non-specific (off-target) effects. Clemastine was docked into the agonist-bound state structure of the receptor (6DK1) with solvation-corrected docking of − 43 kcal/mol | Clemastine inhibited SARS2 replication, reducing supernatant viral RNA load with a promising level of activity with EC50 = 0.95 ± 0.83 µM | - | |
Cloperastine | Cloperastine inhibited SARS-CoV-2 replication by non-specific (off-target) effects | - | - | [182] |
Chlorprothixene | - | Chlorprothixene inhibits the SARS-CoV replication with EC50s around 10 µM | - | [183] |
Chlorpromazine | Chlorpromazine inhibited SARS-CoV-2 replication by non-specific (off-target) effects | Chlorpromazine didn’t inhibit the virus replication | Inhibited viral replication in the lungs but protected against SARS-CoV-2 | |
Clomiphene | - | Clomiphene showed an inhibitory impact with IC50 of 3.32 µM | - | [142] |
Clomipramine | - | Clomipramine showed an IC50 average of 5.63 | - | [184] |
Conessine | - | Show functional inhibition of ASMase with residual ASM activity of 20.8 | - | [27] |
Cyclobenzaprine | - | - | - | |
Cyproheptadine | - | - | - | |
Desipramine | - | Desipramine with concentrations of 5 μM and 35 μM inhibited acid sphingomyelinase activity | - | [186] |
Desloratadine | - | Desloratadine, a commonly used antiallergic, well-tolerated with no major side effects, potently reduced the production of SARS-CoV-2 RNA in Vero-E6 cells | Finally, the ex vivo kinetic of the antiviral effect of desloratadine was evaluated on primary Human Nasal Epithelial Cells (HNEC), showing a significant delay of viral RNA production with a maximal reduction reached after 72 h of treatment | [187] |
Dicycloverine | - | Dicycloverine, showed antiviral efficacy against SARS-CoV-2, reducing viral infection by at least 50%, | - | [188] |
Dilazep | - | - | - | |
Dimebon | - | Inhibited ASMase with residual activity 44.1% | - | [27] |
Doxepine | - | Doxepin could inhibit SARS-CoV-2 spike pseudovirus from entering the ACE2-expressing cell, reducing the infection rate to 25.82% | - | [189] |
Drofenine | - | Drofenine showed an inhibitory impact through pKa alteration of 9.21 | - | [127] |
Emetine | Emetine (P5) showed binding energy to RNA-dependent RNA polymerase (RdRp) enzyme with − 7.81 kcal/mol | Antiviral effect of emetine against SARS-CoV-2 virus in Vero E6 cells with the estimated 50% effective concentration at 0.46 μM | - | |
Fendeline | - | - | - | |
Flupenthixol | Flupenthixol showed docking PLANTS score with RdRp and MPro with − 91.70 and − 91.82, respectively | Antiviral tests using native SARS-CoV-2 virus in Vero E6 cells confirmed that flupenthixol significantly inhibited SARS2 replication, reducing supernatant viral RNA load with a promising activity level | Flupenthixol inhibited viral entry in our lung organoid model | |
Fluoxetine | Fluoxetine demonstrates non-serotonergic, anti-inflammatory effects. Our results show a critical role for IL6 signal transduction protein (IL6ST) and NF-kappaB Subunit 1 (NFKB1) in fluoxetine’s ability to act as a potential therapy for hyperinflammatory states such as asthma, sepsis, and COVID-19 | Fluoxetine with concentrations between 5 μM and 35 μM inhibited acid sphingomyelinase activity | In this multicenter retrospective observational study involving a large sample of patients hospitalized for COVID-19, we found that antidepressant use, at a mean dosage of 21.6 (SD = 14.1) fluoxetine-equivalent milligrams, was significantly and substantially associated with reduced risk of intubation or death, independently of patient characteristics, clinical and biological markers of disease severity, and other psychotropic medications | |
Fluvoxamine | Fluvoxamine reduced the viral infection, as measured by luciferase reporter activity | Treatment of COVID-19 patients with fluvoxamine for 2 weeks also effectively decreased the development of clinical deterioration | ||
Fluphenazine | Fluphenazine revealed the best binding pattern and the highest docking score against the main protease binding site (–11.75 kcal/mol) | Fluphenazine dihydrochloride showed IC50 (Avg) of 6.36 against against SARS-CoV-2 | - | |
Flupentixol | - | - | - | |
Flunarizine | Flunarizine by a spike protein docking screen | Flunarizine showed an impact against SARS-CoV-2, which was confirmed through cytopathic effect (CPE) assay in Vero E6 cells with EC50 (uM) of 10.0 | - | |
Hydroxyzin | The drugs that passed all applied lysosomotropism criteria are azithromycin, promethazine, cyclizine, chloroquine, clemastine, hydroxyzine, rifabutin and vicriviroc, and drugs that do not have data for one of the criteria but passed all the others are chlorcyclizine, homochlorcyclizine and quinacrine | The diphenhydramine, hydroxyzine, and azelastine to exhibit direct antiviral activity against SARS-CoV-2 in vitro | Usage of hydroxyzine was associated with reduced incidence of SARS-CoV-2 positivity in subjects greater than age 61 | |
Imipramine | Inhibitor candidate for SARS-CoV-2 Main Protease | Concentrations between 5 μM and 35 μM inhibited acid sphingomyelinase activity | - | |
Loperamide | - | Loperamide hydrochloride showed antiviral effect against In vitro live virus | - | [179] |
Loratadine | In vitro, severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) spike pseudotyped viral infection experiments indicated that histamine H1 antagonists loratadine (LOR) and desloratadine (DES) could prevent the entry of the pseudotyped virus into ACE2-overexpressing HEK293T cells and showed that DES was more effective | Prior usage of loratadine was associated with a reduced incidence of positive SARS-CoV-2 test results in individuals 61 years and above in a statistically significant manner | ||
Maproteline | - | - | - | |
Melatonine | The establish that a combinatorial drug treatment using melatonin and toremifene will provide an effective therapeutic strategy to mitigate the severity of COVID-19 In summary, combining mercaptopurine and melatonin may offer a potential combination therapy for 2019-nCoV/SARS-CoV-2 by synergistically targeting papain-like protease, ACE2, c-Jun signalling, and anti-inflammatory pathways | The risk was reduced in those who had pneumococcal polysaccharide or influenza vaccine or were on melatonin, paroxetine, or carvedilol | ||
Mebhydroline | - | Mebhydroline causes in vitro inhibition of acid sphingomyelinase | - | [174] |
Mebeverine | - | - | - | |
Mibefradile | - | Mibefradile causes in vitro inhibition of acid sphingomyelinase | - | [174] |
Norfluoxetine | - | - | - | |
Nortriptyline | The potential to reverse transcriptomic signature upon SARS-CoV-2 through acting as an antagonist for Adrenergic uptake inhibitor | - | - | [196] |
Paroxetine | - | - | Most potentially impactful is the reduced risk of testing positive in patients who were on melatonin, carvedilol, and paroxetine, which are drugs identified in drug-repurposing studies to have a potential benefit against COVID-19 | [160] |
Perphenazine | - | - | - | |
Pimozide | Pimozide, tested by computational docking analysis and in vitro assays, has been suggested to inhibit the main protease of SARS-CoV-2 (MPro) | Pimozide, ebastine, and bepridil were the three most potent FDA/EMA-approved medicines, with IC50 values of 42 ± 2, 57 ± 12, and 72 ± 12 µM, respectively Pimozide inhibited the infection by pseudotyped viruses with minimal effects on cell viability | - | |
Pimethexene | - | - | - | |
Profenamine | Profenamine showed binding affinity to ASMase of − 8.7 kcal/mol | - | - | [197] |
Promethazine | -Promethazine showed effectiveness against either SARS-CoV, SARS-CoV-2 or MERS viruses or two or all of them, supporting the potential value of this antiviral strategy -Promethazine is a candidate for targeting COVID-19 Related Genes | Promethazine hydrochloride showed IC50 (avg) of 9.21 μM | - | |
Promazine | - | Promazine was identified as a high-confidence inhibitor of SARS-CoV-2 replication | - | [199] |
Protriptyline | - | - | - | |
Quinacrine | The remaining top candidate drugs identified by our analysis include kinase inhibitors erlotinib, alvocidib, dasatinib, antimalarial quinacrine, and phenothiazine thioridazine, a more commonly used antipsychotic. These drugs also have antiviral properties and are yet to be explored for the treatment of COVID-19 | - | - | [200] |
Sertindole | - | Sertindole showed in vitro inhibition of acid sphingomyelinase | - | [174] |
Solasodine | Solasodine showed a binding affinity of − 8.7 against ASMase | - | - | |
Sertraline | - | Mechanistically, sertraline HCl was found to block SARS-CoV-2 S protein-mediated cell fusion | - | [164] |
Suloctidil | - | - | - | |
Tamoxifene | Overall, we recommend that tamoxifen may protect against cytokine storms, alleviate ARDS in COVID-19 patients, and reduce the incidence of critical illness and mortality | Tamoxifen citrateshowed IC50 (avg) of 34.12 μM | - | |
Thioridazine | Thioridazine and its identified photoproducts (mesoridazine and sulforidazine) have high biological activity on the virus Mpro. This shows that thioridazine and its two photoproducts might represent new potent medicines to be used for treatment in this outbreak - | Thioridazine has anti-SARS-CoV-2 activity in vitro | - | |
Tomatidine | Profenamine showed binding affinity to ASMase of − 8.7 kcal/mol | - | - | |
Terfenadine | - | Terfenadine can reverse the transcriptional landscape induced by SARS-CoV-2 infection when tested on Vero-E6 cells infected with SARS-CoV-2 and on human pluripotent stem-cell-derived pancreatic endocrine organoid cultures | - | [202] |
Trifluoperazine | Trifluoperazine was predicted to bind to Mpro and RdRp (PLANTS scores < − 80.00), thus corroborating putative multimodal actions | Trifluoperazine 2HCl showed antiviral activity against SARS-CoV-2 with CC50 and IC50(μM) of 29.29 and 11.75, respectively | - | |
Triflupromazine | - | The triflupromazine demonstrated antiviral activity in a screen against MERS-CoV replication in Huh-7 cells | - | [24] |
Trimipramine | Amitriptyline showed binding to the allosteric site of SARS-CoV-2 Main Protease with − 5.5 kcal/mol | - | - | [176] |
Zolantidine | - | - | - |