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School of Medicine
Department Affiliation: Primary: Medicine; Secondary: Pharmacology and Molecular Sciences
Degree: M.D., Ph.D., Johns Hopkins University
Telephone Number: 410-955-1888
Fax Number: 410-955-2634
E-mail address: email@example.com
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. and Shapiro, T.A. Molecular and cytotoxic effects of camptothecin, a topoisomerase I inhibitor, on trypanosomes and Leishmania. Proc. Natl. Acad. Sci. USA 92:3726-3730, 1995. Pub Med Reference
- 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
- Arav-Boger, R. and Shapiro, T.A. Molecular mechanisms of resistance in antimalarial chemotherapy: The unmet challenge. Annu. Rev. Pharmacol. Toxicol. 45:565-585, 2005. Pub Med Reference
- Shapiro, T.A. and Goldberg, D. Drugs used in the chemotherapy of protozoal infections: Malaria, Chapter 39, pp. 1021-47 In: Goodman and Gilman's The Pharmacological Basis of Therapeutics. 11th edition (LL Brunton, JS Lazo, KL Parker, eds.) McGraw-Hill, New York NY, 2006.
- Scocca, J.R., Shapiro, T.A. (2008) A mitochondrial topoisomerase IA essential for late theta structure resolution in African trypanosomes. Mol Microbiol. 67:820-9. Pub Med Reference
- Bakshi, R.P., Sang, D., Morrell, A., Cushman, M., Shapiro, T.A. (2009) Activity of indenoisoquinolines against African trypanosomes. Antimicrob Agents Chemother. 53:123-8. Pub Med Reference
- Rosenthal, A.S., Chen, X., Liu, J.O., West, D.C., Hergenrother, P.J., Shapiro, T.A., Posner, G.H. (2009) Malaria-infected mice are cured by a single oral dose of new dimeric trioxane sulfones which are also selectively and powerfully cytotoxic to cancer cells. J Med Chem. 52:1198-203 Pub Med Reference
- Nyunt, M.M., Hendrix, C.W., Bakshi, R.P., Kumar, N., Shapiro, T.A. (2009) 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. Pub Med Reference
- Klingbeil, M.M., Shapiro, T.A. (2009) Unraveling the secrets of regulating mitochondrial DNA replication. Mol Cell 35:398-400 Pub Med Reference
- Tang, S.C., Shapiro, T.A. (2010) Newly identified antibacterial leads are topoisomerase poisons in African trypanosomes. Antimicrob Agents Chemother 54:620-6. PMC2812133 Pub Med Reference