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.

Public Health Relevance

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.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI105106-01A1
Application #
8577786
Study Section
Macromolecular Structure and Function A Study Section (MSFA)
Program Officer
Rogers, Martin J
Project Start
2013-05-29
Project End
2018-04-30
Budget Start
2013-05-29
Budget End
2014-04-30
Support Year
1
Fiscal Year
2013
Total Cost
$347,091
Indirect Cost
$113,208
Name
University of California San Francisco
Department
Pharmacology
Type
Schools of Pharmacy
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Spangler, Benjamin; Kline, Toni; Hanson, Jeffrey et al. (2018) Toward a Ferrous Iron-Cleavable Linker for Antibody-Drug Conjugates. Mol Pharm 15:2054-2059
Blank, Brian R; Gut, Jiri; Rosenthal, Philip J et al. (2017) Enantioselective Synthesis and in Vivo Evaluation of Regioisomeric Analogues of the Antimalarial Arterolane. J Med Chem 60:6400-6407
Aron, Allegra T; Heffern, Marie C; Lonergan, Zachery R et al. (2017) In vivo bioluminescence imaging of labile iron accumulation in a murine model of Acinetobacter baumannii infection. Proc Natl Acad Sci U S A 114:12669-12674
Spangler, Benjamin; Morgan, Charles W; Fontaine, Shaun D et al. (2016) A reactivity-based probe of the intracellular labile ferrous iron pool. Nat Chem Biol 12:680-5
Li, Hao; O'Donoghue, Anthony J; van der Linden, Wouter A et al. (2016) Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530:233-6
Spangler, Benjamin; Fontaine, Shaun D; Shi, Yihui et al. (2016) A Novel Tumor-Activated Prodrug Strategy Targeting Ferrous Iron Is Effective in Multiple Preclinical Cancer Models. J Med Chem 59:11161-11170
Lauterwasser, Erica M W; Fontaine, Shaun D; Li, Hao et al. (2015) Trioxolane-Mediated Delivery of Mefloquine Limits Brain Exposure in a Mouse Model of Malaria. ACS Med Chem Lett 6:1145-9
Fontaine, Shaun D; Spangler, Benjamin; Gut, Jiri et al. (2015) Drug delivery to the malaria parasite using an arterolane-like scaffold. ChemMedChem 10:47-51
Mott, Bryan T; Eastman, Richard T; Guha, Rajarshi et al. (2015) High-throughput matrix screening identifies synergistic and antagonistic antimalarial drug combinations. Sci Rep 5:13891
Fontaine, Shaun D; DiPasquale, Antonio G; Renslo, Adam R (2014) Efficient and stereocontrolled synthesis of 1,2,4-trioxolanes useful for ferrous iron-dependent drug delivery. Org Lett 16:5776-9

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