Faculty

Theresa Shapiro, MD, PhD

"This year the NIH funded our new Clinical Pharmacology Training Program, which is designed to provide young clinician scientists with the tools and experience to discover and develop new therapies, particularly for parasitic infections such as malaria. This program addresses the widely acknowledged manpower gap in translational research, particularly as it relates to the rational development and use of antiparasitic drugs."

The research groups led by Gary Posner and Theresa Shapiro continued their collaborative work to develop effective new antimalarial drugs. Two novel compounds, each a bridged dimer of artemisinin, were synthesized from naturally occurring artemisinin in just four chemical steps. The syntheses were scaled up to obtain multigram quantities in overall yields of 32 percent to 44 percent. Both compounds exhibit potent antimalarial activity in vitro. In rodent models of malaria, both compounds are active when given orally or intravenously, and both are more active and safer than clinically used sodium artesunate. Furthermore, both compounds showed activity in a transgenic adenocarcinoma of mouse prostate model. Compared with non-tumorigenic cell lines, activity was greatest in the aggressive, tumorigenic and metastatic prostate cancer cell lines.

In an effort to accelerate the drug develoment process, the Shapiro lab is evaluating the utility of a novel in vitro system for studying pharmacokinetic/pharmacodynamic (PK/PD) relationships for antimalarial compounds. Although antibacterial activity is recognized to have a critical dependence on concentration-time exposure, little if anything is known about this aspect of antimalarial drug action. Understanding PK/PD relationships leads directly to rational dosing regimens, and can streamline the otherwise necessary empirical dosing evaluations in Phase I human trials.

CONTACT DR. SHAPIRO

Johns Hopkins University
School of Medicine
600 North Wolfe Street
Hunterian Room 301
Baltimore, MD 21287

email:     tshapiro@jhmi.edu
phone:   410-955-1888
fax:       410-955-2634

LINKS

JHMI Faculty Page

SELECTED PUBLICATIONS

Arav-Boger R, Shapiro TA. Molecular mechanisms of resistance in antimalarial chemotherapy: The unmet challenge. ­ Ann Rev Pharmacol and Toxicol 45:565-585, 2005. Abstract

Posner GH, McRiner AJ, Paik I-H, Sur S, Borstnik K, Xie S, Shapiro TA, Alagbala A, Foster B. Anticancer and antimalarial efficacy and safety of artemisinin-derived trioxane dimers in rodents. J Med Chem 47:1299-1301, 2004. Abstract

Bachi MD, Korshin EE, Hoos R, Szpilman AM, Ploypradith P, Xie S, Shapiro TA, Posner GH. A short synthesis and biological evaluation of potent and nontoxic antimalarial bridged bicyclic beta-sulfonyl-endoperoxides. J Med Chem 46:2516-2533, 2003. Abstract

Posner GH, Paik IH, Sur S, McRiner AJ, Borstnik K, Xie S, Shapiro TA. Orally active, antimalarial, anticancer, artemisinin-derived trioxane dimers with high stability and efficacy. J Med Chem 46:1060-1065, 2003. Abstract

Borstnik K, Paik IH, Shapiro TA, Posner GH. Antimalarial chemotherapeutic peroxides: artemisinin, yingzhaosu A and related compounds. Int J Parasitol 32:1661-1667, 2002. Abstract

Posner GH, Jeon HB, Ploypradith P, Paik IP, Borstnik, K, Xie S, Shapiro TA. Orally active, water soluble, antimalarial 3-aryltrioxanes: short synthesis and preclinical efficacy testing in rodents. J Med Chem 45:3824-3828, 2002.

Posner GH, Northrop J, Pail I-K, Bortsnik K, Dolan P, Kensler TW, Xie S, Shapiro TA. New chemical and biological aspects of artemisinin-derived trioxane dimers. Bioorganic and Med Chem 10:227-232, 2002. Abstract

MacDonald SM, Bhisutthibhan J, Shapiro TA, Rogerson SJ, Taylor TE, Tembo M, Langdon JM, Meshnick SR. Immune mimicry in malaria: Plasmodium falciparum secretes a functional histamine-releasing factor homolog in vitro and in vivo. Proc Natl Acad Sci USA 98:10829-10832, 2001. Article

Posner GH, Jeon HB, Parker MH, Krasavin M, Paik I-K, Shapiro TA. Antimalarial simplified 3-aryltrioxanes: synthesis and preclinical efficacy/toxicity testing in rodents. J of Med Chem 44:3054-3058, 2001. Abstract