Theresa A. Shapiro
725 N. Wolfe Street
Baltimore MD 21205
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.
Bakshi, RP, Tatham L, Savage AC, Tripathi AK, Mlambo G, Ippolito MM, Nenortas E, Rannard SP, Owen A, Shapiro TA. Long-acting injectable atovaquone nanomedicines for malaria prophylaxis. Nat Commun, doi 10.1038/s41467-017-02603-z, 2018
Bakshi RP, Nenortas E, Tripathi AK, Sullivan DJ, Shapiro TA. Model system to define pharmacokinetic requirements for antimalarial drug efficacy. Sci Transl Med 5:73-80, 2013
Meyer KJ, Shapiro TA. Potent antitrypanosomal activities of Heat Shock Protein 90 inhibitors in vitro and in vivo. J Infect Dis 208:489-99, 2013
Slack RD, Mott BT, Woodard LE, Tripathi A, Sullivan D, Nenortas E, Girdwood SCT, Shapiro TA, Posner GH. Malaria-infected mice are completely cured by one 6 mg/kg oral dose of a new monomeric trioxane sulfide combined with mefloquine. J Med Chem 55:291-6, 2012
Nyunt MM, Hendrix CW, Bakshi RP, Kumar N, Shapiro TA. Phase I/II evaluation of the prophylactic antimalarial activity of pafuramidine in healthy volunteers challenged with Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 80:528-35, 2009
Klingbeil MM, Shapiro TA. Unraveling the secrets of regulating mitochondrial DNA replication. Mol Cell 35:398-400, 2009
Scocca JR, Shapiro TA. A mitochondrial topoisomerase IA essential for late theta structure resolution in African trypanosomes. Mol Microbiol. 67:820-9, 2008
Bodley AL, Chakraborty AK, Xie S. Burri C.and Shapiro TA. An unusual type IB topoisomerase from African trypanosomes. Proc. Natl. Acad. Sci. USA 100:7539-7544, 2003
Bodley AL.and Shapiro TA. Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania.Proc. Natl. Acad. Sci. USA 92:3726-3730, 1995.