Theresa A. Shapiro

Image of Dr. Theresa Shapiro

Theresa A. Shapiro

Primary Appointment: 
Division of Clinical Pharmacology; Medicine
Secondary Appointment: 
Pharmocology and Molecular Sciences

725 N. Wolfe Street
Hunterian 301 
Baltimore MD 21205

Research topic: 

Discovery, development and clinical trials of drugs for malaria and sleeping sickness; in vitro pharmacokinetics-pharmacodynamics; long-acting chemoprophylaxis

The central theme of our research is antiparasitic chemotherapy. On a molecular basis, we are interested in understanding the mechanism of actionfor existing antiparasitic agents, and in identifying vulnerablemetabolic targets for much-needed, new, antiparasitic chemotherapy.Clinical studies are directed toward an evaluation, in humans, of the efficacy, pharmacokinetics, metabolism, and safety, of experimental antiparasitic drugs. The following are examples of ongoing work.   1. The topoisomerases, "magicians of the cell", catalyze alterations in the topological state of DNA. These reactions are essential for the orderly synthesis of nucleic acids and for cell survival. A number of clinically important antitumor and antibacterial drugs have as their mechanism of action the inhibition of topoisomerase activity. We have found that topoisomerase inhibitors, or gene silencing by means of RNA interference, cause dramatic alterations in the structure and replication of nuclear and mitochondrial DNA in African trypanosomes (the organisms that cause sleeping sickness). We have also found that several of the classical antitrypanosomal drugs inhibit trypanosome topoisomerase activity in vivo. Of considerable importance, the severity of the molecular lesions attributable to enzyme inhibition correlates closely with trypanosome killing.   2. The advent and rapid spread of chloroquine-resistant falciparum malaria is widely regarded as a public health crisis. Safe new antimalarial drugs are urgently needed. Atovaquone, a broad-spectrum antiprotozoal agent, is almost unique in its dual action against both tissue and bloodstream stages of the malaria parasite. We conducted a prospective, double-blind, placebo-controlled clinical trial which demonstrated that atovaquone can protect healthy volunteers against Plasmodium falciparum. The study used a highly sensitive polymerase chain reaction assay to detect subclinical parasitemia and to distinguish between the two possible mechanisms for prophylaxis.     

Selected Publications: 

Caton E, Nenortas E, Bakshi RP, Shapiro TA. Hollow fiber methodology for pharmacokinetic/pharmacodynamic studies of antimalarial compounds. Curr Protoc Chem Biol, 8:29-58, 2016

Tang-Girdwood SC, Nenortas E, Shapiro TA. Targeting the gyrase of Plasmodium falciparum with topoisomerase poisons. Biochem Pharmacol 95:227-37, 2015

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.