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.
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Shapiro TA, Ranasinha CD, Kumar N, and Barditch-Crovo P (1999) Prophylactic activity of atovaquone against Plasmodium falciparum in humans. Am J. Trop. Med. Hyg. 60: 831-836. View on Pubmed
Ye L, Dinkova-Kostova AT, Wade KL, Zhang Y, Shapiro TA, Talalay P (2002) Quantitative determination of dithiocarbamates in human plasma, serum, erythrocytes and urine: pharmacokinetics of broccoli sprout isothiocyanates in humans. Clin Chim Acta. Feb 316(1-2):43-53. Erratum in Clin Chim Acta 2002 Jul: 321 (1-2) 127-9 View on Pubmed
Bodley AL, Chakraborty AK, Xie S, Burri C, Shapiro TA. (2003) An unusual type IB topoisomerase from African trypanosomes. Proc Natl Acad Sci USA. Jun 24; 100 (13) 7539-7544. View on Pubmed
Nenortas E, Kulikowicz T, Burri C, Shapiro TA. (2003) Antitrypanosomal activities of fluoroquinolones with pyrrolidinyl substitutions. Antimicrob Agents Chemother Sep; 47 (9): 3015-3017. View on Pubmed
Arav-Boger R, Shapiro TA. (2004) Molecular mechanisms of resistance in antimalarial chemotherapy: the unmet challenge. Annu Rev Pharmacol Toxicol Oct 07 (Epub ahead of print) View on Pubmed
Posner GH, McRiner AJ, Paik JH, Sur S, Borstnik K, Xie S, Shapiro TA, Alagbala A, Foster B. (2004) Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimmers in rodents. J Med Chem Feb 26: 47(5): 1299-301. View on Pubmed