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• W4284698352 endingPage "115154" @default.
• W4284698352 startingPage "115154" @default.
• W4284698352 abstract "The development of resistance to current antimalarial therapies remains a significant source of concern. To address this risk,newdrugswithnoveltargetsin distinct developmental stages ofPlasmodiumparasites are required. In the current study,we have targetedP. falciparumTubulin(PfTubulin)proteins which represent some of thepotentialdrug targetsfor malaria chemotherapy. PlasmodialMicrotubules (MTs) play a crucial role during parasite proliferation, growth, and transmission, which render them highlydesirabletargets for the development ofnext-generation chemotherapeutics. Towards this,we have evaluated the antimalarial activity ofTubulintargetingcompounds received from theMedicines for Malaria Venture (MMV)Pathogen Boxagainst the human malaria parasite,P. falciparumincluding 3D7 (chloroquine and artemisinin sensitive strain), RKL-9 (chloroquine-resistant strain), and R539T (artemisinin-resistant strain). At nanomolar concentrations, the filtered-out compounds exhibitedpronouncedmultistage antimalarialeffects across the parasite life cycle, including intra-erythrocytic blood stages, liver stage parasites, gametocytes, and ookinetes. Concomitantly, these compoundswere found toimpedemale gamete ex-flagellation, thus showingtheir transmission-blocking potential. Target mining of these potent compounds, by combining in silico, biochemical and biophysical assays,implicatedPfTubulinas their moleculartarget, which may possibly act bydisruptingMT assembly dynamics by binding at the interface of α-βTubulin-dimer.Further, the promising ADME profile of the parent scaffold supported its consideration as a lead compound for further development.Thus, our work highlights the potential of targetingPfTubulin proteins in discovering and developing next-generation, multistage antimalarial agents against Multi-Drug Resistant (MDR) malaria parasites." @default.
• W4284698352 created "2022-07-08" @default.
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• W4284698352 date "2022-09-01" @default.
• W4284698352 modified "2023-10-03" @default.
• W4284698352 title "Multistage and transmission-blocking tubulin targeting potent antimalarial discovered from the open access MMV pathogen box" @default.
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• W4284698352 doi "https://doi.org/10.1016/j.bcp.2022.115154" @default.
• W4284698352 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/35798201" @default.
• W4284698352 hasPublicationYear "2022" @default.
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