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J Med Chem. 2019 Oct 24;62(20):9217-9235. doi: 10.1021/acs.jmedchem.9b01099. Epub 2019 Oct 14.

Development of Chemical Entities Endowed with Potent Fast-Killing Properties against Plasmodium falciparum Malaria Parasites.

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Tres Cantos, Medicines Development Campus, DDW, GlaxoSmithKline , Severo Ochoa 2 , 28760 Tres Cantos , Madrid , Spain.
Biomedical Sciences Research Center "Alexander Fleming" , Fleming 34 Street , 16672 Vari , Greece.
Faculty of Infectious and Tropical Diseases , London School of Hygiene & Tropical Medicine , London WC1E 7HT , U.K.
Cellzome GmbH, a GlaxoSmithKline Company , Meyerhofstrasse 1 , 69117 Heidelberg , Germany.
LifeArc, Accelerator Building, Open Innovation Campus , Stevenage SG1 2FX , U.K.


One of the attractive properties of artemisinins is their extremely fast-killing capability, quickly relieving malaria symptoms. Nevertheless, the unique benefits of these medicines are now compromised by the prolonged parasite clearance times and the increasing frequency of treatment failures, attributed to the increased tolerance of Plasmodium falciparum to artemisinin. This emerging artemisinin resistance threatens to undermine the effectiveness of antimalarial combination therapies. Herein, we describe the medicinal chemistry efforts focused on a cGMP-dependent protein kinase (PKG) inhibitor scaffold, leading to the identification of novel chemical entities with very potent, similar to artemisinins, fast-killing potency against asexual blood stages that cause disease, and activity against gametocyte activation that is required for transmission. Furthermore, we confirm that selective PKG inhibitors have a slow speed of kill, while chemoproteomic analysis suggests for the first time serine/arginine protein kinase 2 (SRPK2) targeting as a novel strategy for developing antimalarial compounds with extremely fast-killing properties.

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