Malaria causes over a million preventable deaths annually, primarily among children in developing regions of the world. Current World Health Organization (WHO) recommended treatment for malaria involves combinations of an artemisinin-based therapy with a second agent of a distinct therapeutic class. This proposal seeks to establish proof-of-principle in animals for a new approach to deliver artemisinin combination therapy. Specifically, the proposed therapeutic strategy involves parasite-specific delivery of the second partner drug only after entry into the malaria parasite and only after the artemisinin-like activity has been conferred. Using this new approach, it should be possible to prevent patient exposure to the partner agent in its native form and this in principle could improve the safety profiles of existing antimalarial drugs or enable the widespread use of existing drugs that while effective, have serious side effects.

Hemoglobin-digesting parasites, including the malaria parasites Plasmodium falciparum and Plasmodium vivax generate significant concentrations of free ferrous iron heme, which is formed as a result of hemoglobin catabolism by the parasite. These reactive forms of iron present an opportunity for iron(II)-targeted drug delivery, since free forms of ferrous iron are exceedingly rare in healthy tissue and cells. We have developed and validated in animals an iron(II)-targeted drug delivery technology for delivery of therapeutics to the malaria parasites, or more generally, to any biological compartment containing unbound ferrous iron. Drug delivery strategies have scarcely been investigated in anti-parasitic therapy but these approaches have the potential to target parasites selectively, protecting the patient from exposure to active drug species and possibly allowing the safe use of a broader range of therapeutics. Our delivery systems are comprised of a 1,2,4-trioxolane ring system as an iron(II)-sensing 'trigger' moiety and a 'traceless' linker to which the partner drug is attached an ultimately released via a -elimination reaction. The chemical design is such that drugs from a wide swath of chemical and therapeutic target space can in principle be delivered using the approach. In preliminary work, we synthesized prototypical delivery systems and demonstrated the iron(II)-dependent and parasite-selective delivery of a cysteine inhibitor to Plasmodium berghei parasites in infected mice. The goals of the proposed research are to evaluate in animals a new generation of more drug-like delivery systems, and to identify partner drug species that are optimally suited for this new approach to antimalarial therapy. Malaria causes over a million preventable deaths annually, primarily among children in developing regions of the world. Artemisinin combination therapy is the current standard of care treatment for malaria. We have developed a new approach to antimalarial therapy in which the artemisinin partner drug is released only after entry into the malaria parasite and only after the artemisinin-like activity has been conferred. Using this new approach, it is possible to significantly reduce exposure to the partner drug in its native form an this in principle could improve the safety and effectiveness of existing antimalarial drugs. This proposal seeks to further refine our drug delivery approach and to identify partner drugs that are well suited for this approach.