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Theresa A. Shapiro
Department Affiliation: Primary: Medicine; Secondary: Pharmacology and Molecular Sciences
Degree: M.D., Ph.D., Johns Hopkins University
Telephone Number: 410-955-1888
E-mail address: firstname.lastname@example.org
School of Medicine Address: 311-A Biophysics Building, 725 N. Wolfe St., Baltimore, MD 21205
Clinical pharmacology; molecular mechanisms of antiparasitic drug action; effects of topoisomerase inhibitors on DNA of trypanosomes; structure-activity of synthetic antimalarial trioxanes.
The central theme of our research is antiparasitic chemotherapy. On a molecular basis, we are interested in understanding the mechanism of action for existing antiparasitic agents, and in identifying vulnerable metabolic 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.
- 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.
- 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.
- Bodley, A.L., Chakraborty, A.K., Xie, S., Burri, C. and Shapiro, T.A. An unusual type IB topoisomerase from African trypanosomes. Proc. Natl. Acad. Sci. USA 100:7539-7544, 2003. Pub Med Reference
- Scocca, J.R., Shapiro, T.A. A mitochondrial topoisomerase IA essential for late theta structure resolution in African trypanosomes. Mol Microbiol. 67:820-829 ,2008. Pub Med Reference
- Nyunt, M.M., Hendrix, C.W., Bakshi, R.P., Kumar, N., Shapiro, T.A. Phase I/II evaluation of the prophylactic antimalarial activity of pafuramidine in healthy volunteers challenged with Plasmodium falciparum sporozoites. Am J Trop Med Hyg. 80:528-535, 2009. Pub Med Reference
- Slack, R.D., Mott, B.T., Woodard, L.E., Tripathi, A., Sullivan, D., Nenortas, E., Girdwood, S.C., Shapiro T.A., Posner, G.H. 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. 55:291-296, 2012. Pub Med Reference
- Meyer, K.J., Shapiro, T.A. Potent antitrypanosomal activities of heat shock protein 90 inhibitors in vitro and in vivo. J Infect Dis. 208:489-499, 2013. Pub Med Reference
- Bakshi, R.P., Nenortas, E., Tripathi, A.K., Sullivan, D.J., Shapiro, T.A. Model system to define pharmacokinetic requirements for antimalarial drug efficacy. Sci Transl Med. 5(205):205ra135, 2013. Pub Med Reference
- Tang Girdwood, S.C., Nenortas, E., Shapiro, T.A. Targeting the gyrase of Plasmodium falciparum with topoisomerase poisons. Biochem Pharmacol. 95:227-237, 2015. Pub Med Reference
- Bakshi, R.P., Tatham, L.M., Savage, A.C., Tripathi, A.K., Mlambo, G., Ippolito, M.M., Nenortas, E., Rannard, S.P., Owen, A., Shapiro, T.A. Long-acting injectable atovaquone nanomedicines for malaria prophylaxis. Nat Commun. 9(1):315, 2018. Pub Med Reference
- Meyer, K.J., Meyers, D.J., Shapiro, T.A. Optimal kinetic exposures for classic and candidate antitrypanosomals. J Antimicrob Chemother. 74:2303-2310, 2019. Pub Med Reference
- Caton, E., Nenortas, E., Bakshi, R.P., Shapiro, T.A. Kinetic Driver of Antibacterial Drugs against Plasmodium falciparum and Implications for Clinical Dosing. Antimicrob Agents Chemother. 2019 63(11), 2019. pii: e00416-19. Pub Med Reference