Iron-Dependent Drug Delivery as a New Paradigm in Anti-Parasitic Chemotherapy and Prophylaxis

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Investigator: Adam R. Renslo, PhD
Sponsor: Bill & Melinda Gates Foundation

Location(s): United States

Description

My research group is engaged at the interface of chemistry and biology. As medicinal chemists, we design and synthesize small molecules (about 25 to 75 atoms) that modulate disease pathology at the level of the enzyme, cell, and whole animal, with current projects in cancer, infectious disease, and neurodegeneration.  Using such small molecule probes, we are exploring the mechanisms underlying the action of artemisinin and related antimalarial drugs. Finally, we are inventing and employing new platform technologies in an effort to expand the realm of druggable target space and drug-like chemical space. These technologies include fragment-based approaches to target protein-protein interfaces and allosteric modulation of enzymes, the use of novel unnatural amino acids to discover cell-permeable peptides, and new targeted prodrug approaches in cancer and infectious disease.

This project is an  evaluation of ferrous-iron targeted drug delivery that exploits the high ferrous iron concentrations in malaria parasites 

Modern drug discovery is founded on the notion of selective drug action at a single target as a means to maximize efficacy while minimizing the potential for off-target effects (toxicity). In treating infectious disease and cancer, however, the objective is to kill a particular subset of cells amidst a population of normal cells. The challenge with multi-targeted therapeutics and cytotoxic agents then becomes one of selectively delivering the drug to its intended site(s) of action. 

To address this problem, we are exploring small molecule based drug-targeting technologies. For example, we have devised iron(II)-reactive molecules that deliver a tethered drug species selectively to cellular compartments possessing aberrant quantities of reactive ferrous iron. Such reactive iron species are produced during the blood-stages of malaria infection as the parasite catabolizes host hemoglobin. In collaboration with the Bogyo Lab (Stanford University) we have demonstrated in cell culture and in mice that such molecules can release a drug payload in an iron(II)-dependent fashion.