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.
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
BACK TO ARTICLETable 1. Twenty-three active compounds that block Ebola VLP entry into HeLa cells.
| 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.
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.
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