Open AccessLead Optimization of Dehydroemetine for Repositioned Use in Malaria
Author(s) -
Priyanka Panwar,
Kepa K. Burusco,
Muna Abubaker,
Holly Matthews,
Andrey Gutnov,
Elena FernándezÁlvaro,
Richard A. Bryce,
James A. Wilkinson,
Niroshini Nirmalan
Publication year - 2020
Publication title -
antimicrobial agents and chemotherapy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.07
H-Index - 259
eISSN - 1070-6283
pISSN - 0066-4804
DOI - 10.1128/aac.01444-19
Subject(s) - emetine , plasmodium falciparum , pharmacology , artemisinin , drug , malaria , multiple drug resistance , drug resistance , chloroquine , artesunate , medicine , biology , microbiology and biotechnology , immunology
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 [IC 50 ], 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 (IC 50 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 (IC 50 , 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.