Structure-Based Strategy for Targeting Dormant Malaria

Malaria affects an estimated 280 million people worldwide every year. In 2023, the disease killed nearly 600,000 people according to the World Health Organization. A major challenge to eradicating the disease is eliminating the dormant (“hypnozoite”) form of the malaria-causing parasite Plasmodium vivax. Hypnozoites can persist in the liver for years, reactivating to a symptomatic, transmissible blood form. Current hypnozoite-targeting drugs (primaquine and tafenoquine) are contraindicated during pregnancy, in children, and in people with G6PD deficiency, a hereditary genetic disorder that is common in areas with high malaria prevalence. Thus, 30% of people worldwide cannot take these medicines.

Dr. Alexis Kaushansky

Infectious disease expert Alexis Kaushansky, PhD, and structural biologist Bart Staker, PhD, have respective expertise in malaria and structure-based drug design. They are collaborating on a new class of antimalarial therapies — inhibitors of N-myristoyltransferase (NMT), which is an essential eukaryotic protein-modifying enzyme.

Dr. Staker leads studies to optimize NMT-inhibitor drug candidates, using his expertise in structural methods for rational drug design. To increase selectivity for the Plasmodium enzyme over the human enzyme, Dr. Staker and team co-crystallize promising lead compounds with human or parasite enzymes. The researchers use the resulting structural information on interactions between drug candidates and enzyme active sites to modify and test the drugs for specificity and effectiveness, including against dormant parasites.

The research team identified drug candidates with powerful dose-dependent effects of 90% or higher inhibition of liver-stage and blood-stage parasitic growth but with minimal cytotoxicity to human hepatocytes. NMT inhibitors of the human enzyme have been investigated 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 for the human NMT. These findings suggest that Plasmodium-specific inhibitors will be effective and safe in humans.  

Dr. Bart Staker

The parasite-specific NMT inhibitors are unique in interrupting multiple stages of the Plasmodium life cycle, because most available malarial drugs target only the blood stage. This property gives the new antimalarial drug candidates the potential to break the malarial cycle of infection-dormancy-relapse/reactivation. Such drugs are an urgently needed addition to the antimalarial arsenal, as resistance to existing drugs spreads. Drs. Kaushansky and Staker have preliminary data supporting pathogen-selective NMT inhibitors as treatments for other parasitic diseases as well, including cryptosporidiosis, toxoplasmosis, and leishmaniasis.

Drs. Kaushansky and Staker seek partnerships to further advance their next-generation antimalarial drugs. They have expertise in compound modification, structural analysis of compounds complexed with targets, and assays for quantifying interference with all Plasmodium forms. They have mouse models for investigating potential effectiveness against malaria symptoms and dormant phase reactivation in patients.

Stage of Development

• Preclinical in vitro

Partnering Opportunities

• Collaborative research on preclinical development
• Structure-based drug design and optimization
• Lead compound development
• Sponsored research agreement
• Consultation agreement

Publications

Mendez A, Bolling C, Taylor S … Staker B. Structure of Plasmodium vivax N-myristoyltransferase with inhibitor IMP-1088: exploring an NMT inhibitor for antimalarial therapy. Acta Crystallogr F Struct Biol Commun. 2025;81(Pt 1):1-10.

Rodríguez-Hernández D, Fenwick MK, Zigweid R … Kaushansky A, Staker BL, et al. Exploring subsite selectivity within Plasmodium vivax N-myristoyltransferase using pyrazole-derived inhibitors. J Med Chem. 2024;67(9):7312-7329.

Bolling C, Mendez A, Taylor S … Staker B, et al. Ternary structure of Plasmodium vivax N-myristoyltransferase with myristoyl-CoA and inhibitor IMP-0001173. Acta Crystallogr F Struct Biol Commun. 2024;80(Pt 10):269-277.

Fenwick MK, Reers AR, Liu Y … Kaushansky A … Staker BL. Identification of and structural insights into hit compounds targeting N-myristoyltransferase for Cryptosporidium drug development. ACS Infect Dis. 2023;9(10):1821-1833.

Rodríguez-Hernández D, Vijayan K, Zigweid R … Staker BL, Kaushansky A, et al. Identification of potent and selective N-myristoyltransferase inhibitors of Plasmodium vivax liver stage hypnozoites and schizonts. Nat Commun. 2023;14(1):5408.

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.