Ebola Virus Bayesian Machine Learning Models Enable New in Vitro Leads

Anantpadma, Manu; Lane, Thomas R.; Zorn, Kimberley M.; Lingerfelt, Mary A.; Clark, Alex M.; Freundlich, Joel S.; Davey, Robert A.; Madrid, Peter B.; Ekins, Sean

doi:10.1021/acsomega.8b02948

Cited by 55 publications

(67 citation statements)

References 80 publications

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“…This model predicted Ebola inhibitory activity for tilorone, which was then tested using an in vitro anti-Ebola assay for activity. Tilorone gave a 50% effective concentration (EC 50 ) in this assay of 230 nM (Table II), making it one of the most potent small-molecule inhibitors of EBOV reported at the time (31,35,36). After a series of toxicity and pharmacokinetic studies, the compound was tested in a mouse model of EBOV infection where it was associated with 90-100% survival in a mouse EBOV efficacy study at three different doses.…”

Section: Introductionmentioning

confidence: 99%

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

2020

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Section: Introductionmentioning

confidence: 99%

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

2020

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“…Efforts to improve the efficiency and cost effectiveness of EBOV drug discovery have involved our efforts to identify several molecules using ML which have progressed through in vitro and in vivo testing (12-15, 17, 51). We have also previously used these ML models to predict in vitro efficacy for drugs that were then tested against EBOV (12,22). The mechanism for these three compounds against EBOV is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…The Assay Central software has been previously described (23)(24)(25)(26)(27)(28)(29)(30)(31)(32) which uses the source code management system Git to gather and store structure-activity datasets collated in Molecular Notebook (Molecular Materials Informatics, Inc. in Montreal, Canada). The output is a high-quality dataset and a Bayesian model using extendedconnectivity fingerprints of maximum diameter 6 (ECFP6) descriptors.…”

Section: Lysosomotropic Machine Learning Modelmentioning

confidence: 99%

“…In addition, pyronaridine is used as an antimalarial in combination with artesunate (Pyramax®). We had previously determined that artesunate also has micromolar in vitro inhibitory activity against EBOV (22). We now assess whether pyronaridine accumulates in lysosomes and if there is any effect with artesunate or its active metabolite dihydroartemisinin against EBOV when combined with pyronaridine in vitro.…”

Section: Introductionmentioning

confidence: 99%

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Repurposing Pyramax® for the Treatment of Ebola Virus Disease: Additivity of the Lysosomotropic Pyronaridine and Non-Lysosomotropic Artesunate

Lane¹,

Dyall²,

Luke³

et al. 2020

Preprint

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We have recently identified three molecules (tilorone, quinacrine and pyronaridine tetraphosphate) which all demonstrated efficacy in the mouse model of infection with mouse-adapted Ebola virus (EBOV) model of disease and had similar in vitro inhibition of an Ebola pseudovirus (VSV-EBOV-GP), suggesting they interfere with viral entry.Using a machine learning model to predict lysosomotropism these compounds were evaluated for their ability to inhibit via a lysosomotropic mechanism in vitro. We now demonstrate in vitro that pyronaridine tetraphosphate is an inhibitor of Lysotracker accumulation in lysosomes (IC 50 = 0.56 μM). Further, we evaluated synergy between pyronaridine and artesunate (Pyramax®), which are used in combination to treat malaria. Artesunate was not found to have lysosomotropic activity in vitro and the combination effect on EBOV inhibition was shown to be additive. Pyramax® may represent a unique example of the repurposing of a combination product for another disease.

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“…All of these molecules inhibited EBOV in HeLa cells but not Vero cells, and they all demonstrated significant in vivo activity in the mouse-adapted EBOV (ma-EBOV) efficacy model (23–25). Pyronaridine (EC 50 range of 420 nM-1.14 µ M (22, 26)) has been previously described in detail (27). It is the major component of the EU-approved antimalarial Pyramax, which is a combination antimalarial therapy with artesunate and pyronaridine and is approved for this use in the Democratic Republic of the Congo as well as other countries (e.g.…”

Section: Introductionmentioning

confidence: 99%

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

Lane

Massey²,

Comer³

et al. 2020

Preprint

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31The recent outbreaks of the Ebola virus (EBOV) in Africa have brought global visibility to 32 the shortage of available therapeutic options to treat patients infected with this or closely 33 related viruses. We have recently computationally identified three molecules which have 34 all demonstrated statistically significant efficacy in the mouse model of infection with 35 mouse adapted Ebola virus (ma-EBOV). One of these molecules is the antimalarial 36 pyronaridine tetraphosphate (IC 50 range of 0.82-1.30 µM against three strains of EBOV 37 and IC 50 range of 1.01-2.72 µM against two strains of Marburg virus (MARV)) which is 38 an approved drug in the European Union and used in combination with artesunate. To 39 date, no small molecule drugs have shown statistically significant efficacy in the guinea 40 pig model of EBOV infection. Pharmacokinetics and range-finding studies in guinea pigs 41 directed us to a single 300mg/kg or 600mg/kg oral dose of pyronaridine 1hr after 42 infection. Pyronaridine resulted in statistically significant survival of 40% at 300mg/kg 43 and protected from a lethal challenge with EBOV. In comparison, oral favipiravir (300 44 mg/kg dosed once a day) had 43.5 % survival. The in vitro metabolism and metabolite 45 identification of pyronaridine and another of our EBOV active molecules, tilorone, which 46 suggests significant species differences which may account for the efficacy or lack 47 thereof, respectively in guinea pig. In summary, our studies with pyronaridine 48 demonstrates its utility for repurposing as an antiviral against EBOV and MARV, 49 providing justification for future testing in non-human primates. 50 51 52 4 Importance 53There is currently no antiviral small molecule drug approved for treating Ebola Virus 54 infection. We have previously used machine learning models to identify new uses for 55 approved drugs and demonstrated their activity against the Ebola virus in vitro and in 56 vivo. We now describe the pharmacokinetic properties of the antimalarial pyronaridine in 57 the guinea pig. In addition, we show that this drug is effective against multiple strains of 58 EBOV and MARV in vitro and in the guinea pig model of Ebola virus infection. These 59 combined efforts indicate the need to further test this molecule in larger animal efficacy 60 studies prior to clinical use in humans. These findings also may be useful for 61 repurposing this drug for use against other viruses in future. 62 63

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Ebola Virus Bayesian Machine Learning Models Enable New in Vitro Leads

Cited by 55 publications

References 80 publications

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

Tilorone: a Broad-Spectrum Antiviral Invented in the USA and Commercialized in Russia and beyond

Repurposing Pyramax® for the Treatment of Ebola Virus Disease: Additivity of the Lysosomotropic Pyronaridine and Non-Lysosomotropic Artesunate

Pyronaridine Tetraphosphate Efficacy Against Ebola Virus Infection in Guinea Pig

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