Panwar, P, Burusco, KK, Abubaker, M, Matthews, H, Gutnov, A, Fernández-Álvaro, E, Bryce, RA, Wilkinson, J and Nirmalan, N (2020) Lead Optimization of Dehydroemetine for Repositioned Use in Malaria. Antimicrobial Agents and Chemotherapy, 64 (4). ISSN 0066-4804

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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.

Item Type: Article
Additional Information: This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license.
Uncontrolled Keywords: malaria, antimalarial drug interactions, SYBR green flow cytometry, emetine, dehydroemetine, drug discovery, repositioning
Subjects: Q Science > Q Science (General)
Divisions: Faculty of Natural Sciences > School of Life Sciences
Related URLs:
Depositing User: Symplectic
Date Deposited: 18 May 2022 16:33
Last Modified: 18 May 2022 16:33

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