Department Affiliation: Primary: Medicine; Secondary: Pharmacology and Molecular Sciences
Degree: M.D., Ph.D., Johns Hopkins University
Rank: Professor
Telephone Number: 410-955-1888
Fax Number: 410-955-2634
E-mail address: tshapiro@jhmi.edu
School of Medicine Address: 301 Hunterian 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.
Representative Publications:
- 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
- Posner, G.H., Park, S.B., Gonzalez, L., Wang, D., Cumming, J.N., Klinedinst, D., Shapiro, T.A., and Bachi, M.D. Evidence for the importance of high-valent Fe=O and of a diketone in the molecular mechanism of action of antimalarial trioxane analogs of artemisinin, J. Am. Chem. Soc. 118:3537-3538, 1996. Pub Med Reference not available.
- Shapiro, T.A., Ranasinha, C.D., Kumar, N., and Barditch-Crovo, P. Prophylactic activity of atovaquone against Plasmodium falciparum in humans, Am. J. Trop. Med. Hyg. 60:831-836, 1999. Pub Med Reference
- Nenortas, E., Burri, C., and Shapiro, T.A. Antitrypanosomal activity of fluoroquinolones, Antimicrob. Agents Chemother 43:2066-2068, 1999. 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
- Nenortas, E., Kulikowicz, T., Burri, C., and Shapiro, T.A. Antitrypanosomal activity of fluoroquinolones with pyrrolidinyl substitutions, Antimicrob. Agts. Chemothera 47:3015-3017, 2003. Pub Med Reference
- Posner, G.H., McRiner, A.J., Paik, I.-H., Sur, S., Borstnik, K., Xie, S., Shapiro, T.A., Alagbala, A., and Foster, B. Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents, J. Med. Chem. 47:1299-1301, 2004. Pub Med Reference
Bakshi, R. and Shapiro, T.A. RNA interference of Trypanosoma brucei topoisomerase IB: Both subunits are essential, Mol. Biochem. Parasitol. 136:249-255, 2004. 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.
Other graduate programs in which Dr. Shapiro participates:
