Lead Optimization of Dehydroemetine for Repositioned Use in Malaria

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 [IC 50 ], 47 nM Ϯ 2.1 nM [mean Ϯ standard deviation]). Dehydroemetine, a synthetic analogue of emetine dihydrochloride, has been reported to have lesscardiotoxic 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 (Ϫ)-R,S-dehydroemetine mimicked the bound pose of emetine more closely than did (Ϫ)-S,S-dehydroisoemetine. (Ϫ)-R,Sdehydroemetine (IC 50 71.03 Ϯ 6.1 nM) was also found to be highly potent against the multidrug-resistant K1 strain of P. falciparum compared with (Ϫ)-S,S-dehydroisoemetine (IC 50 , 2.07 Ϯ 0.26 M), 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 (Ϫ)-R,S-dehydroemetine to have synergistic antimalarial activity with atovaquone and proguanil. Emetine dihydrochloride and (Ϫ)-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.

Dissecting translation elongation dynamics through ultra-long tracking of single ribosomes

“…The ribosome is a frequent target of small molecules produced by a variety of microorganisms. Ribosome targeting molecules are widely used in biomedical research to experimentally modulate translation elongation dynamics and also as therapeutic agents in the clinic (Carocci and Yang, 2016; Lin et al, 2018; Panwar et al, 2020). While the precise mechanism of action has been resolved from a structural perspective for a small number of ribosome targeting drugs (i.e., identification of the binding site on ribosomes (Garreau de Loubresse et al, 2014; Schneider-Poetsch et al, 2010)), the effects of these drugs on translation elongation dynamics in vivo are poorly understood.…”

Mechanisms of antiviral action and toxicities of ipecac alkaloids: Emetine and dehydroemetine exhibit anti-coronaviral activities at non-cardiotoxic concentrations

“…The antiparasitic activities of emetine and DHE are attributed to inhibition of protein synthesis ( Entner and Grollman, 1973 ). Emetine and DHE interact with the E-site located in the 40S subunit of the Plasmodium falciparum ribosome and thereby inhibit peptide chain translocation ( Wong et al., 2014 ; Dmitriev et al., 2020 ; Panwar et al., 2020 ). In contrast, there is minimal consensus on how these therapeutic agents exert their biological activity as antiviral drugs.…”

“…The synthetic analog, dehydroemetine (DHE), elicits lower cardiotoxicity than emetine ( Dempsey and Salem, 1966 ), presumably due to a shorter half-life in heart tissues ( Schwartz and Herrero, 1965 ). Due to its reduced cardiotoxicity, potent activity against Plasmodium species, and its in vitro synergism with chloroquine ( Wong et al., 2014 ), atovaquone, and proguanil ( Panwar et al., 2020 ) in vitro , DHE has been considered for the treatment of malaria ( Wong et al., 2014 ; Panwar et al., 2020 ). The effectiveness of DHE as an antiviral agent for the treatment of coronavirus diseases is yet to be established.…”

Boswellia carterii oleoresin extracts induce caspase-mediated apoptosis and G1 cell cycle arrest in human leukaemia subtypes

“…The effect of the B. carterii oleoresin methanolic extract on leukaemia mitochondrial membrane potential (Δψ m ) was evaluated by flow cytometry as previously described by Panwar et al (2020) . Cell densities of 100,000 cells were incubated for 24–72 h with 25–100 μg/ml B. carterii oleoresin extract, a vehicle control (0.5% v/v DMSO) or a positive control (the oxidative phosphorylation uncoupler carbonyl cyanide 3-chlorophenylhydrazone (CCCP) (Sigma Aldrich, United States).…”