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.

Drug NameBlock Ebola VLP entryCytotoxicitySelectivityApproved indicationMOA
IC50(µM)IC90(µM)Max. Inh. (%)IC50 (µM)Index (fold)
Vinblastine0.0480.13087>500>10 324AnticancerMicrotubule inhibitor
Vinorelbine/Navelbine0.0660.19090>500>7546AnticancerMicrotubule inhibitor
Vincristine0.1410.25883>500>3554AnticancerMicrotubule inhibitor
Colchicine0.2380.35473>500>2097Primary for goutMicrotubule inhibitor
Nocodazole*0.4021.0487>500>1242AnticancerMicrotubule inhibitor
Toremifene0.5663.7398180316AnticancerEstrogen receptor modulator
Tamoxifen0.7343.159799.8135AnticancerEstrogen receptor modulator
Digoxin0.7633.4568250327AntiarrhythmicNa+-K+ pump inhibitor
Clemastine1.103.769895.687Antiallergic, hay fever, rhinitisHistamine antagonist
Raloxifene/Evista1.849.01100>500>271AnticancerEstrogen receptor modulator
Sunitinib1.913.829014877AnticancerKinase inhibitor
Thiothixene1.927.1810070.136AntipsychoticDopamine antagonist
Dronedarone2.203.518148.021AntiarrhythmicMultichannel blocker
Maprotiline2.4412.110014660AntidepressantAdrenergic uptake inhibitors and histamine antagonist
Daunomycin2.635.4098>500>190AnticancerTopoisomerase Inhibitor
Benztropine2.648.2510025095Anticholinergic, antihistamineHistamine antagonist and Cholinergic antagonist
Azithromycin2.7915.8100>500>179AntimicrobialProtein synthesis inhibitor
Mebendazole3.4414.088>500>145AntihelminthicMicrotubule inhibitor
Trifluoperazine4.4812.09797.021Antipsychotic, antiemeticDopamine antagonist
Clarithromycin4.5315.1100>500>110AntimicrobialProtein synthesis inhibitor
Albendazole4.9020.776>500>102AnthelminticMicrotubule inhibitor
Clomipramine4.9911.79364.112AntidepressantSerotonin uptake inhibitors and histamine antagonist
Propafenone6.2523.8100>500>80AntiarrhythmicSodium 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 NameBlock Ebola VLP entryCytotoxicitySelectivityApproved indicationMOA
IC50(µM)IC90(µM)Max. Inh. (%)IC50 (µM)Index (fold)
Carfilzomib0.4321.8857>500>1156AnticancerProteasome Inhibitor
Deslanoside0.48511.766250515AntiarrhythmicNa+-K+ pump inhibitor
Maduramicin0.6113.9410424.340AntimicrobialIonophore
Cepharanthine1.534.4011288.958Anti-inflammatory/AntineoplasticRelease of neutrophil elastase inhibitor
Clomiphene(Clomifene)1.725.349291.453Female infertilityEstrogen receptor modulator
Oxibendazole1.723.7557>500>291AnthelminticDNA Polymerase Inhibitor
Daunorubicin2.434.4596250103Antimicrobial/anticancerDNA Topoisomerase II inhibitor
Niclosamide2.666.6081>500>188AntihelminticSTAT-3 Inhibitor
Zoloft (sertraline)2.739.087973.227AntidepressantSerotonin reuptake inhibitor
Mefloquine2.7313.09443.216AntimalarialHemozoin formation inhibitor
Tilorone3.4319.0100>500>146AntiviralDNA Polymerase Inhibitor
Bazedoxifene3.432.638943.213Postmenopausal osteoporosisEstrogen receptor modulator
Topotecan3.8510.8107>500>130AnticancerDNA Topoisomerase I Inhibitor
Bosutinib3.8521.310143.211AnticancerBcr-Abl inhibitor
Thioproperazine4.3212.5103>500>116AntipsychoticPostsynaptic receptors modulator
Spiramycin4.3211.792>500>116AntimicrobialProtein synthesis inhibitor
Mibefradil4.327.349643.210AntihypertensiveCalcium channel blocker
Amodiaquine4.4327.3106>500>113AntimalarialHistamine N-methyltransferase inhibitor
Nitrovin4.857.1495>500>103AntimicrobialIonophore
Bifemelane4.8518.19925052AntidepressantCholinergic system modulator
Bitolterol6.1122.68525041BronchodilatorBeta-adrenergic receptor agonist
Proglumetacin6.8517.393>500>73Anti-inflammatoryCyclooxygenase-1 inhibitor
Aprindine7.6926.693>500>65AntiarrhythmicNa+-K+ pump inhibitor
Cyclomethycaine7.6919.686>500>65AnestheticNa+-K+ pump inhibitor
Posaconazole7.698.3377>500>65AntifungalMembrane-bound enzyme inhibitor
Alverine Citrate8.6321.890>500>58AntispasmodicParasympathetic nervous system modulator
Azaclorzine9.4337.188>500>53AntianginalBeta-adrenergic receptor agonist
Salmeterol9.6813.090>500>52AntiasthmaBeta-adrenergic receptor agonist
Piperacetazine9.6818.190>500>52AntipsychoticDopamine antagonist
Gefitinib9.6817.993>500>52AnticancerEGFR inhibitor
Imipramine13.752.2102>500>36AntidepressantSerotonin norepinephrine reuptake inhibitor
Chloroquine15.313398>500>32AntimalarialHemozoin formation inhibitor
Nilotinib24.310410050.12AnticancerTyrosine 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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