The novel research, carried out on a small number of non-human primates, could bolster efforts to develop more potent therapies against one of the world's leading killers. The study, published in the November 11, 2011 issue of PLoS ONE, was led by senior author Vern Schramm, Ph.D., professor and Ruth Merns Chair in Biochemistry at Einstein.
Malaria is a mosquito-borne disease caused by single-celled parasites belonging to the Plasmodium genus. The U.S. Centers for Disease Control and Prevention estimated that in 2008 (the latest year for which figures are available) between 190 million and 311 million cases of malaria occurred worldwide and between 708,000 and 1.003 million people died, most of them young children in sub-Saharan Africa. Plasmodium falciparum, the malaria species most likely to cause severe infections and death, is very common in many countries in Africa south of the Sahara desert.
The Einstein researchers exploited what is arguably P. falciparum's Achilles' heel: it can't synthesize purines, vital building blocks for making DNA. Instead, the parasite must make purines indirectly, by using an enzyme called purine nucleoside phosphorylase (PNP) to make a purine precursor called hypoxanthine. By inhibiting PNP, the drug BCX4945 kills the parasites by starving them of the purines they need to survive.
After BCX4945 showed potency against laboratory cultures of P. falciparum, owl monkeys were chosen as the non-human primate model for further testing of the drug. Three animals were infected with a strain of P. falciparum that is consistently lethal without antimalarial therapy. Orally administering BCX4945 twice a day for seven days cleared the infections from all the animals between the fourth and seventh day of treatment. The monkeys remained parasite-negative for up to nine days post-treatment. Parasitic infection eventually returned in all three monkeys after treatment ended, although a lower rate of parasitic growth was observed. No signs of toxicity were observed during the study period (30 days after the first dose).
BCX4945 belongs to a class of drugs known as transition state analogs that Dr. Schramm has been developing since 1994. Transition states form in every chemical change and whenever an enzyme does its job of converting one chemical (the substrate) into another (the product). The fleeting transition-state molecule is neither substrate nor product, but something in between—a ghostly intermediate to which the enzyme clings for just one billionth of a millionth of a second.
After figuring out the brief-lived transition-state structure for a particular enzyme, Dr. Schramm is able to design transition-state analogs to knock that enzyme out of action. The analogs closely resemble the actual transition-state structure but with one big difference: they powerfully inhibit the enzyme by binding to it and not letting go.
The transition-state analog BCX4945 was chosen for this study because of its high affinity for both P. falciparum PNP and human PNP (which the parasite obtains from the red blood cells it infects). Since PNP is abundant in mammalian red blood cells and those cells are constantly replaced, BCX4945 is toxic only to the parasite and not its mammalian hosts. (Two of Dr. Schramm's other PNP inhibitors—one for T-cell cancers, the other for gout—are being evaluated in clinical trials.)
"Inhibiting PNP differs from all other current approaches for treating malaria," said Dr. Schramm. "For that reason, BCX4945 fits well with the current World Health Organization protocols for malaria treatment, which call for using combination-therapy approaches against the disease."
The paper is titled "Plasmodium falciparum Parasites Are Killed by a Transition State Analogue of Purine Nucleoside Phosphorylase in a Primate Animal Model." Other Einstein researchers involved in the study were Steven Almo, Ph.D., lead author Maria Cassera, Ph.D. (now at Virginia Polytechnic Institute and State University), Keith Hazleton, M.D./Ph.D. candidate, Emilio Merino (now at Virginia Polytechnic Institute and State University), Meng-Chiao Ho, Ph.D., (now at Academia Sinica), Andrew Murkin, Ph.D., (now at SUNY Buffalo), and Jemy Gutierrez, Ph.D., (now at Pfizer). This research was supported primarily by the National Institute of Allergy and Infectious Disease, part of the National Institutes of Health, and early aspects of the study were funded by Medicines for Malaria.
About Albert Einstein College of Medicine of Yeshiva University
Albert Einstein College of Medicine of Yeshiva University is one of the nation's premier centers for research, medical education and clinical investigation. During the 2011-2012 academic year, Einstein is home to 724 M.D. students, 248 Ph.D. students, 117 students in the combined M.D./Ph.D. program, and 368 postdoctoral research fellows. The College of Medicine has 2,522 full time faculty members located on the main campus and at its clinical affiliates. In 2011, Einstein received nearly $170 million in awards from the NIH. This includes the funding of major research centers at Einstein in diabetes, cancer, liver disease, and AIDS. Other areas where the College of Medicine is concentrating its efforts include developmental brain research, neuroscience, cardiac disease, and initiatives to reduce and eliminate ethnic and racial health disparities. Its partnership with Montefiore Medical Center, the University Hospital and academic medical center for Einstein, advances clinical and translational research to accelerate the pace at which new discoveries become the treatments and therapies that benefit patients. Through its extensive affiliation network involving Montefiore and four other medical centers in the Bronx, Manhattan and Long Island, Einstein runs one of the largest post-graduate medical training programs in the United States, offering approximately 155 residency programs to more than 2,200 physicians in training. For more information, please visit www.einstein.yu.edu and follow us on Twitter @EinsteinMed.
Kim Newman | EurekAlert!
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