The Open University ’ s repository of research publications and other research outputs Spiroindolone NITD 609 is a novel antimalarial drug that targets the P - type ATPase

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. Optimisation 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. Key Terms  Apicomplexan organisms: a group of parasitic eukaryotic microorganisms that includes Plasmodium and Toxoplasma.  Malaria box: an open access collection of 400 structurally diverse antimalarial compounds selected from whole-cell drug screen hits. It consists of 200 drug-like compounds and 200 probe-like compounds, all with unknown mechanism of action.  NGBS Consortium: public-private collaboration involved in a malaria drug discovery programme to identify new chemotypes for the development of malaria treatments.  P-type adenosine triphosphatase (P-type ATPase): a family of evolutionary related membrane-bound pumps that self-phosphorylate at a conserved aspartate residue. Most P-type ATPases pump cations enabling the maintenance of electrochemical gradients across cell membranes.  Plasmodium bergei: a murine malaria widely used in an animal model for malaria research.  Spiroindolones (Spirotetrahydro beta-carbolines): synthetic compound with two stereocentres consisting of a beta-carboline structure connected through a central spiroatom to an indole structure.