1. Academic Validation
  2. Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

  • Antimicrob Agents Chemother. 2020 Mar 24;64(4):e01444-19. doi: 10.1128/AAC.01444-19.
Priyanka Panwar 1 Kepa K Burusco 2 Muna Abubaker 1 Holly Matthews 3 Andrey Gutnov 4 Elena Fernández-Álvaro 5 Richard A Bryce 2 James Wilkinson 1 Niroshini Nirmalan 6
Affiliations

Affiliations

  • 1 Environment and Life Sciences, University of Salford, Greater Manchester, United Kingdom.
  • 2 Division 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.
  • 3 Keele University, Newcastle-under-Lyme, Staffordshire, United Kingdom.
  • 4 Chiroblock GMBH, Wolfen, Germany.
  • 5 GlaxoSmithKline, Diseases of the Developing World Medicines Development Campus, Tres Cantos, Spain.
  • 6 Environment and Life Sciences, University of Salford, Greater Manchester, United Kingdom n.j.nirmalan@salford.ac.uk.
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.

Keywords

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

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