title: Spiroindolone NITD609 is a novel antimalarial drug that targets the P-type ATPase PfATP4.
abstract: Malaria is caused by the Plasmodium parasite and is a major health problem leading to many deaths worldwide. Lack of a vaccine and increasing drug resistance highlights the need for new antimalarial drugs with novel targets. Antiplasmodial activity of spiroindolones was discovered through whole-cell, phenotypic screening methods. Optimization of the lead spiroindolone improved both potency and pharmacokinetic properties leading to drug candidate NITD609 which has produced encouraging results in clinical trials. Spiroindolones inhibit PfATP4, a P-type Na(+)-ATPase in the plasma membrane of the parasite, causing a fatal disruption of its sodium homeostasis. Other diverse compounds from the Malaria Box appear to target PfATP4 warranting further research into its structure and binding with NITD609 and other potential antimalarial drugs.
authors.affiliation: Department of Life, Health & Chemical Sciences, The Open University, Walton Hall, Milton Keynes, MK7 6AA, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Turner
mesh_terms: D000251:Adenosine Triphosphatases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D027682:Cation Transport Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006207:Half-Life; D006801:Humans; D007211:Indoles / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D008288:Malaria / Q000188:drug therapy; D008862:Microsomes, Liver / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013141:Spiro Compounds / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D000962:Antimalarials; D027682:Cation Transport Proteins; D007211:Indoles; C552304:NITD 609; D015800:Protozoan Proteins; D013141:Spiro Compounds; D000251:Adenosine Triphosphatases; C021838:sodium-translocating ATPase
keywords: KAE609; NIDT609; PfATP4; Plasmodium; cipargamin; malaria; spiroindolone