Bioactivity Comments

The interaction table below provides data from whole cell assays and gives the antiparasite activity of cipargamin against a number of Plasmodium lifecycle stages. The results include an evaluation of asexual blood stage activity using a panel of culture-adapted P. falciparum strains, with cipargamin demonstrating no evidence of reduced potency against drug resistant strains. In addition, ex vivo testing of field-isolates from regions with known chloroquine resistance has shown potent asexual blood stage activity for both P. falciparum and P. vivax (IC50 <10nM) [3].

Whole organism assay data
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MOA/likely target Sp. Assay description Type Action Value Parameter Concentration range (M) Reference Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖ Parasite growth inhibition assay - - 9.3 pIC50 - 3 ⤷ pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfTM90C2A Plasmodium falciparum TM90C2A P. falciparum TM90C2A (PfTM90C2A) is a clinical isolate, first described during a Phase 2 clinical trial to determine atovaquone efficacy in Thailand (PMID:8651372). PfTM90C2A is sensitive to atovaquone. ✖ Parasite growth inhibition assay - - 9.3 pIC50 - 3 ⤷ pIC50 9.3 (IC50 5x10-10 M) [3H]-hypoxanthine incorporation assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfK1 Plasmodium falciparum K1 P. falciparum strain K1 (PfK1) was isolated in Kanchanaburi, Thailand in 1979. PfK1 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be a multidrug-resistant strain. ✖ Parasite growth inhibition assay - - 9.2 pIC50 - 3 ⤷ pIC50 9.2 (IC50 6x10-10 M) [3H]-hypoxanthine incorporation assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase Pf3D7 Plasmodium falciparum 3D7 P. falciparum strain 3D7 (Pf3D7) was derived from isolate NF54 by limiting dilution. The complete genome of Pf3D7 has been sequenced (GenBank: LN999946.1). Pf3D7 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖ Parasite growth inhibition assay - - 9.1 pIC50 - 3 ⤷ pIC50 9.1 (IC50 7x10-10 M) [3H]-hypoxanthine incorporation assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfW2 Plasmodium falciparum W2 P. falciparum strain W2 (PfW2) was cloned from the Indochina III/CDC isolate, originally derived from a Laotian patient who failed chloroquine therapy. PfW2 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and susceptible to mefloquine. ✖ Parasite growth inhibition assay - - 9.1 pIC50 - 3 ⤷ pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [3] Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfTM91C235 Plasmodium falciparum TM91C235 P. falciparum TM91C235 (PfTM91C235) is a clinical isolate from a patient in Thailand who failed mefloquine treatment twice. It can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine, sulfadoxime, pyrimethamine and quinine. ✖ Parasite growth inhibition assay - - 9.1 pIC50 - 3 ⤷ pIC50 9.1 (IC50 9x10-10 M) [3H]-hypoxanthine incorporation assay [3] Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfD6 Plasmodium falciparum D6 P. falciparum strain D6 (PfD6) was collected in Sierra Leone. PfD6 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is generally considered drug sensitive with minor mefloquine resistance. ✖ Parasite growth inhibition assay - - 9.0 pIC50 - 3 ⤷ pIC50 9.0 (IC50 1x10-9 M) [3H]-hypoxanthine incorporation assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase Pf7G8 Plasmodium falciparum 7G8 P. falciparum strain 7G8 (Pf7G8) was subcloned from the IMTM22 strain by limiting dilution. The original IMTM22 strain was isolated from a 12 year old male near Manaus, Brazil in 1980. Pf7G8 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4). This strain is a gametocyte producer and is reported to be chloroquine-sensitive and pyrimethamine-resistant. ✖ Parasite growth inhibition assay - - 8.9 pIC50 - 3 ⤷ pIC50 8.9 (IC50 1.2x10-9 M) [3H]-hypoxanthine incorporation assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfV1/S Plasmodium falciparum V1/S P. falciparum strain V1/S (PfV1/S) is an in vitro culture-adapted clone of V1, that originated in Vietnam. PfV1/S can be obtained from the Malaria Research and Reference Reagent Resource Center (MR4) and is reported to be resistant to chloroquine and quinine. ✖ Parasite growth inhibition assay - - 8.9 pIC50 - 3 ⤷ pIC50 8.9 (IC50 1.4x10-9 M) [3H]-hypoxanthine incorporation assay [3] Lifecycle stages: Plasmodium asexual blood stage (erythrocytic merozoite, trophozoite, erythrocytic schizont) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖ Parasite early stage (I–II) gametocyte assay - - - - - 7 ⤷ Giemsa-stained blood film counts: dose-dependent, significant inhibition of stage II gametocyte development [7] Lifecycle stages: Plasmodium sexual blood stage (gametocyte) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖ Parasite late stage (III–V) gametocyte assay - - - - - 7 ⤷ Giemsa-stained blood film counts: dose-dependent, inhibition of stage V gametocyte development [7] Lifecycle stages: Plasmodium sexual blood stage (gametocyte) Plasmodium falciparum non-SERCA-type Ca2+ -transporting P-ATPase PfNF54 Plasmodium falciparum NF54 P. falciparum strain NF54 (PfNF54) was derived from a patient who had never left the Netherlands. PfNF54 can be obtained from the European Malaria Reagent Repository or the Malaria Research and Reference Reagent Resource Center (MR4) and is sensitive to a panel of antimalarial compounds including chloroquine and pyrimethamine. ✖ Standard membrane feeding assay (SMFA) - - - - - 7 ⤷ Oocyst count: significantly reduced count observed with the addition of cipargamin when compared to control feeds [7] Lifecycle stages: Plasmodium mosquito host stage (gametocyte, gamete, zygote, ookinete, oocyst, sporozoite)