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Pharmacology

Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

Priyanka Panwar, Kepa K. Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernández-Álvaro, Richard A. Bryce, James Wilkinson, Niroshini Nirmalan
Priyanka Panwar
aEnvironment and Life Sciences, University of Salford, Greater Manchester, United Kingdom
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Kepa K. Burusco
bDivision of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
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Muna Abubaker
aEnvironment and Life Sciences, University of Salford, Greater Manchester, United Kingdom
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Holly Matthews
cKeele University, Newcastle-under-Lyme, Staffordshire, United Kingdom
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Andrey Gutnov
dChiroblock GMBH, Wolfen, Germany
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Elena Fernández-Álvaro
eGlaxoSmithKline, Diseases of the Developing World Medicines Development Campus, Tres Cantos, Spain
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Richard A. Bryce
bDivision of Pharmacy and Optometry, School of Health Sciences, Faculty of Biology, Medicine and Health, Manchester Academic Health Science Centre, University of Manchester, Manchester, United Kingdom
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James Wilkinson
aEnvironment and Life Sciences, University of Salford, Greater Manchester, United Kingdom
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Niroshini Nirmalan
aEnvironment and Life Sciences, University of Salford, Greater Manchester, United Kingdom
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DOI: 10.1128/AAC.01444-19
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ABSTRACT

Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel antimalarial treatments. The antiamoebic compound emetine dihydrochloride has been identified as a potent in vitro inhibitor of the multidrug-resistant strain K1 of Plasmodium falciparum (50% inhibitory concentration [IC50], 47 nM ± 2.1 nM [mean ± standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have less-cardiotoxic effects than emetine. The structures of two diastereomers of dehydroemetine were modeled on the published emetine binding site on the cryo-electron microscopy (cryo-EM) structure with PDB code 3J7A (P. falciparum 80S ribosome in complex with emetine), and it was found that (−)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than did (−)-S,S-dehydroisoemetine. (−)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (−)-S,S-dehydroisoemetine (IC50, 2.07 ± 0.26 μM), which loses its potency due to the change of configuration at C-1′. In addition to its effect on the asexual erythrocytic stages of P. falciparum, the compound exhibited gametocidal properties with no cross-resistance against any of the multidrug-resistant strains tested. Drug interaction studies showed (−)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (−)-R,S-dehydroemetine failed to show any inhibition of the hERG potassium channel and displayed activity affecting the mitochondrial membrane potential, indicating a possible multimodal mechanism of action.

  • Copyright © 2020 Panwar et al.

This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.

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Lead Optimization of Dehydroemetine for Repositioned Use in Malaria
Priyanka Panwar, Kepa K. Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernández-Álvaro, Richard A. Bryce, James Wilkinson, Niroshini Nirmalan
Antimicrobial Agents and Chemotherapy Mar 2020, 64 (4) e01444-19; DOI: 10.1128/AAC.01444-19

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Lead Optimization of Dehydroemetine for Repositioned Use in Malaria
Priyanka Panwar, Kepa K. Burusco, Muna Abubaker, Holly Matthews, Andrey Gutnov, Elena Fernández-Álvaro, Richard A. Bryce, James Wilkinson, Niroshini Nirmalan
Antimicrobial Agents and Chemotherapy Mar 2020, 64 (4) e01444-19; DOI: 10.1128/AAC.01444-19
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KEYWORDS

malaria
antimalarial drug interactions
SYBR green flow cytometry
emetine
dehydroemetine
drug discovery
repositioning

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