Lead optimisation of dehydroemetine for repositioned use in malaria

Panwar, P, Burusco, KK, Abubaker, M, Matthews, H, Gutnov, A, Fernández-Álvaro, E, Bryce, RA, Wilkinson, JA ORCID: https://orcid.org/0000-0003-1300-6017 and Nirmalan, NJ ORCID: https://orcid.org/0000-0001-9000-298X 2020, 'Lead optimisation of dehydroemetine for repositioned use in malaria' , Antimicrobial Agents and Chemotherapy, 64 (4) , pp. 1-10.

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Drug repositioning offers an effective alternative to de novo drug design to tackle the urgent need for novel anti-malarial treatments. The anti-amoebic compound, emetine dihydrochloride, has been identified as a potent in-vitro inhibitor of the multi-drug resistant strain K1 of Plasmodium falciparum (IC50: 47 nM ± 2.1 nM). 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 modelled on the published emetine binding site on cryo-EM structure 3J7A (Pf 80S ribosome in complex with emetine) and it was found that (-)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than (-)-S,S-dehydroisoemetine. (-)-R,S-dehydroemetine (IC50 71.03 ± 6.1 nM) was also found to be highly potent against the multi-drug resistant K1 strain of P. falciparum in comparison 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 compounds exhibited gametocidal properties with no cross-resistance against any of the multi-drug 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 on the mitochondrial membrane potential indicating a possible multi-modal mechanism of action. [Abstract copyright: Copyright © 2020 Panwar et al.]

Item Type: Article
Additional Information: ** From PubMed via Jisc Publications Router **Journal IDs: eissn 1098-6596 **Article IDs: pubmed: 31964796; pii: AAC.01444-19 **History: published 21-01-2020
Schools: Schools > School of Environment and Life Sciences
Journal or Publication Title: Antimicrobial Agents and Chemotherapy
Publisher: American Society for Microbiology
ISSN: 0066-4804
Related URLs:
Funders: University of Salford
SWORD Depositor: Publications Router
Depositing User: Publications Router
Date Deposited: 05 Feb 2020 09:35
Last Modified: 16 Feb 2022 03:58
URI: https://usir.salford.ac.uk/id/eprint/56368

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