In vitro, 53 existing *licensed* drugs have activity against Ebola virus entry into cells/ Emerging Microbes and Infections, a Nature publication

Yesterday, authors from the NIH, NY and Toronto published a paper describing their screening system for compounds against Ebola.  The method has identified a large number of approved substances with potential benefits. Many of them have been mentioned in this blog previously, such as clomifene, antimalarials and antiarrhythmics.  Ninety-five additional compounds were also found to have in vitro activity against Ebola, but are not licensed drugs.

One weakness of this paper is the absence (a consequence of the screening method used) of any information about the therapeutic drug level needed for anti-Ebola activity. Some of the active drugs found, such as digoxin and anticancer drugs, have narrow therapeutic to toxic windows (and are therefore likely to be toxic), whereas other anti-Ebola drugs found, such as antihistamines, have wide therapeutic to toxic ratios and are likely to be well tolerated, even in patients with extremely unstable conditions.  


There is also an absence of any sense of how effective any of the drugs may turn out to be.

Now rapid animal testing is needed and then hopefully careful human clinical trials can commence.  It is exciting that many disciplines have turned their spotlights (and tool chests) on the myriad problems that need to be solved to conquer to Ebola epidemic.

TABLE 1

FROM:

Identification of 53 compounds that block Ebola virus-like particle entry via a repurposing screen of approved drugs

Jennifer Kouznetsova, Wei Sun, Carles Martínez-Romero, Gregory Tawa, Paul Shinn, Catherine Z Chen, Aaron Schimmer, Philip Sanderson, John C McKew, Wei Zheng and Adolfo García-Sastre

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Table 1. Twenty-three active compounds that block Ebola VLP entry into HeLa cells.

Figures and tables index

Drug Name Block Ebola VLP entry Cytotoxicity Selectivity Approved indication MOA
IC50(µM) IC90(µM) Max. Inh. (%) IC50 (µM) Index (fold)
Vinblastine 0.048 0.130 87 >500 >10 324 Anticancer Microtubule inhibitor
Vinorelbine/Navelbine 0.066 0.190 90 >500 >7546 Anticancer Microtubule inhibitor
Vincristine 0.141 0.258 83 >500 >3554 Anticancer Microtubule inhibitor
Colchicine 0.238 0.354 73 >500 >2097 Primary for gout Microtubule inhibitor
Nocodazole*† 0.402 1.04 87 >500 >1242 Anticancer Microtubule inhibitor
Toremifene† 0.566 3.73 98 180 316 Anticancer Estrogen receptor modulator
Tamoxifen† 0.734 3.15 97 99.8 135 Anticancer Estrogen receptor modulator
Digoxin 0.763 3.45 68 250 327 Antiarrhythmic Na+-K+ pump inhibitor
Clemastine 1.10 3.76 98 95.6 87 Antiallergic, hay fever, rhinitis Histamine antagonist
Raloxifene/Evista† 1.84 9.01 100 >500 >271 Anticancer Estrogen receptor modulator
Sunitinib 1.91 3.82 90 148 77 Anticancer Kinase inhibitor
Thiothixene 1.92 7.18 100 70.1 36 Antipsychotic Dopamine antagonist
Dronedarone 2.20 3.51 81 48.0 21 Antiarrhythmic Multichannel blocker
Maprotiline 2.44 12.1 100 146 60 Antidepressant Adrenergic uptake inhibitors and histamine antagonist
Daunomycin 2.63 5.40 98 >500 >190 Anticancer Topoisomerase Inhibitor
Benztropine 2.64 8.25 100 250 95 Anticholinergic, antihistamine Histamine antagonist and Cholinergic antagonist
Azithromycin 2.79 15.8 100 >500 >179 Antimicrobial Protein synthesis inhibitor
Mebendazole 3.44 14.0 88 >500 >145 Antihelminthic Microtubule inhibitor
Trifluoperazine 4.48 12.0 97 97.0 21 Antipsychotic, antiemetic Dopamine antagonist
Clarithromycin 4.53 15.1 100 >500 >110 Antimicrobial Protein synthesis inhibitor
Albendazole 4.90 20.7 76 >500 >102 Anthelmintic Microtubule inhibitor
Clomipramine 4.99 11.7 93 64.1 12 Antidepressant Serotonin uptake inhibitors and histamine antagonist
Propafenone 6.25 23.8 100 >500 >80 Antiarrhythmic Sodium channel blocker
 Abbreviations: MOA, mechanism of action; IC90, inhibitory concentration of 90%; Max. Inh., maximal inhibition.
* The compound was not the original hit but was added for confirmation.
† These compounds were previously reported to be active in Ebola assays.
Figures and tables index

Table 2. An additional 30 active compounds that block Ebola VLP entry in our assay at an IC50<10 and="" nbsp="" si="">10 plus three additional active compounds previously shown to inhibit Ebola virus infection.

Drug Name Block Ebola VLP entry Cytotoxicity Selectivity Approved indication MOA
IC50(µM) IC90(µM) Max. Inh. (%) IC50 (µM) Index (fold)
Carfilzomib 0.432 1.88 57 >500 >1156 Anticancer Proteasome Inhibitor
Deslanoside 0.485 11.7 66 250 515 Antiarrhythmic Na+-K+ pump inhibitor
Maduramicin 0.611 3.94 104 24.3 40 Antimicrobial Ionophore
Cepharanthine† 1.53 4.40 112 88.9 58 Anti-inflammatory/Antineoplastic Release of neutrophil elastase inhibitor
Clomiphene†(Clomifene) 1.72 5.34 92 91.4 53 Female infertility Estrogen receptor modulator
Oxibendazole 1.72 3.75 57 >500 >291 Anthelmintic DNA Polymerase Inhibitor
Daunorubicin 2.43 4.45 96 250 103 Antimicrobial/anticancer DNA Topoisomerase II inhibitor
Niclosamide 2.66 6.60 81 >500 >188 Antihelmintic STAT-3 Inhibitor
Zoloft† (sertraline) 2.73 9.08 79 73.2 27 Antidepressant Serotonin reuptake inhibitor
Mefloquine 2.73 13.0 94 43.2 16 Antimalarial Hemozoin formation inhibitor
Tilorone 3.43 19.0 100 >500 >146 Antiviral DNA Polymerase Inhibitor
Bazedoxifene 3.43 2.63 89 43.2 13 Postmenopausal osteoporosis Estrogen receptor modulator
Topotecan 3.85 10.8 107 >500 >130 Anticancer DNA Topoisomerase I Inhibitor
Bosutinib 3.85 21.3 101 43.2 11 Anticancer Bcr-Abl inhibitor
Thioproperazine 4.32 12.5 103 >500 >116 Antipsychotic Postsynaptic receptors modulator
Spiramycin 4.32 11.7 92 >500 >116 Antimicrobial Protein synthesis inhibitor
Mibefradil 4.32 7.34 96 43.2 10 Antihypertensive Calcium channel blocker
Amodiaquine† 4.43 27.3 106 >500 >113 Antimalarial Histamine N-methyltransferase inhibitor
Nitrovin 4.85 7.14 95 >500 >103 Antimicrobial Ionophore
Bifemelane 4.85 18.1 99 250 52 Antidepressant Cholinergic system modulator
Bitolterol 6.11 22.6 85 250 41 Bronchodilator Beta-adrenergic receptor agonist
Proglumetacin 6.85 17.3 93 >500 >73 Anti-inflammatory Cyclooxygenase-1 inhibitor
Aprindine 7.69 26.6 93 >500 >65 Antiarrhythmic Na+-K+ pump inhibitor
Cyclomethycaine 7.69 19.6 86 >500 >65 Anesthetic Na+-K+ pump inhibitor
Posaconazole 7.69 8.33 77 >500 >65 Antifungal Membrane-bound enzyme inhibitor
Alverine Citrate 8.63 21.8 90 >500 >58 Antispasmodic Parasympathetic nervous system modulator
Azaclorzine 9.43 37.1 88 >500 >53 Antianginal Beta-adrenergic receptor agonist
Salmeterol 9.68 13.0 90 >500 >52 Antiasthma Beta-adrenergic receptor agonist
Piperacetazine 9.68 18.1 90 >500 >52 Antipsychotic Dopamine antagonist
Gefitinib 9.68 17.9 93 >500 >52 Anticancer EGFR inhibitor
Imipramine† 13.7 52.2 102 >500 >36 Antidepressant Serotonin norepinephrine reuptake inhibitor
Chloroquine† 15.3 133 98 >500 >32 Antimalarial Hemozoin formation inhibitor
Nilotinib† 24.3 104 100 50.1 2 Anticancer Tyrosine kinase inhibitor
 Abbreviation: EGFR, epidermal growth factor receptor.
† These compounds were previously reported to be active in Ebola virus infection assays or animal models.
Figures and tables index

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