Structure-Based Strategy for Targeting Dormant Malaria
Generating highly selective inhibitors of Plasmodium N-myristoyltransferase
Malaria affects about 240 million people worldwide every year, killing hundreds of thousands. A major challenge to eradicating the disease is that the malaria-causing parasite Plasmodium vivax has a dormant, hypnozoite form. Hypnozoites can persist in the liver for years, reactivating to a symptomatic, transmissible blood form. Current hypnozoite-targeting drugs (primaquine and tafenoquine) are contraindicated in pregnancy, children, and people with G6PD deficiency, which is common in areas with high malaria prevalence: 30% of people cannot take these drugs.
Drs. Kaushansky and Staker, with respective expertise in malaria and structure-based drug design, are collaborating on a new class of antimalarial therapies — inhibitors of N-myristoyltransferase (NMT), an essential eukaryotic protein-modifying enzyme. Previous NMT inhibitors had effects on both the parasite and human enzymes, but the researchers have overcome this challenge.
Starting with an existing Plasmodium NMT inhibitor, the scientists used X-ray co-crystallization with the parasite enzyme to iteratively alter this lead compound toward greater specificity for the Plasmodium over the human enzyme. In vitro assays showed powerful, dose-dependent effects of 90% or higher inhibition of liver-stage and blood-stage parasitic growth. Cytotoxicity to human hepatocytes was minimal.
NMT inhibitors of the human enzyme are in clinical trials as anticancer therapies, suggesting the general safety of this class of compounds. The most promising antimalarial compound so far from the Kaushansky and Staker collaboration is 270-times more specific for the Plasmodium NMT than the human NMT. These findings suggest that Plasmodium-specific inhibitors will be effective and safe in humans.
The parasite-specific NMT inhibitors are unique in interrupting multiple stages of the Plasmodium life cycle, as most available malarial drugs target only the blood stage. This property gives the new antimalarial drugs the potential to break the malarial cycle of infection-dormancy-relapse/reactivation. They would be an urgently needed addition to the antimalarial arsenal, as resistance to existing drugs spreads.
Antifungals are another potential application of pathogen-selective NMT inhibitors. The principles used to develop antimalarial NMT inhibitors could also be applied to drugs for other parasitic diseases including cryptosporidiosis and leishmaniasis.
Drs. Kaushansky and Staker are seeking partnerships to further advance their next-generation antimalarial drugs. They have knowledge about the lead compounds and ways to increase their effectiveness and specificity. They have expertise in compound modification, structural analysis of compounds complexed with targets, and assays for measuring effects on enzymes of all Plasmodium forms and stages. For future testing and optimization, they have the expertise and facilities to use mouse models to quantitatively determine in vivo effects, including on malaria symptoms and dormant phase reactivation.
Stage of Development
- Preclinical in vitro
- Collaborative research and development on preclinical development
- Structure-based drug design and optimization
- Lead compound development
- Sponsored research agreement
- Consultation agreement
Vijayan K, Wei L, Glennon EKK…Staker B, Kaushansky A. Host-targeted Interventions as an Exciting Opportunity to Combat Malaria. Chem Rev. 2021;121(17):10452-10468.
Harupa A, De Las Heras L, Colmenarejo G, Staker BL…Kaushansky A.Identification of Selective Inhibitors of Plasmodium N-Myristoyltransferase by High-Throughput Screening. J Med Chem. 2020;63(2):591-600.
Schlott AC, Mayclin S, Reers AR…Staker BL, et al. Structure-Guided Identification of Resistance Breaking Antimalarial N‑Myristoyltransferase Inhibitors. Cell Chem Biol. 2019; 18;26(7):991-1000.e7.