Theresa A. Shapiro

The central theme of our research is chemotherapy of malaria and African sleeping sickness. On a molecular basis, we are interested in understanding the mechanism of action for existing agents, and in identifying vulnerable targets for much-needed new chemotherapy. Clinical studies are directed toward evaluating, in humans, the efficacy, pharmacokinetics, metabolism, and safety, of experimental drugs. The following are illustrative. 1) Topoisomerases, “the cell’s magicians”, are essential for the orderly synthesis of nucleic acids and for cell survival. Topoisomerase inhibitors, or its silencing by means of RNA interference, create dramatic alterations in the structure and replication of nuclear and mitochondrial DNA in African trypanosomes (that cause sleeping sickness). Furthermore, several clinically used antitrypanosomals inhibit trypanosome topoisomerases in vivo, and severity of the resulting molecular lesions correlates closely with killing potency. 2) We have devised new methods to mimic in vitro the normal fluctuations of drug levels in vivo. This translational methodology reveals the pharmacokinetic driver of antimalarial or antitrypanosomal drug action, provides a new criterion by which to judge new drug candidates, and makes possible the rational choice of drug combinations, all without resorting to animal or human studies. 3) Safe new antimalarials are urgently needed to replace drugs compromised by resistance. Atovaquone is remarkable for its dual action against both tissue and bloodstream stages of the malaria parasite. We conducted an investigator-initiated prospective, double-blind, placebo-controlled clinical trial, deemed pivotal by FDA, demonstrating that atovaquone protects healthy volunteers against Plasmodium falciparum. Subsequent studies in mice have shown that protection by atovaquone can be extended from one day to weeks, by the injection of slow-release nanoformulations.