Features | Partner Sites | Information | LinkXpress
Sign In
PZ HTL SA
GLOBETECH PUBLISHING
GLOBETECH PUBLISHING

Modified Osteoporosis Drugs Kill Malaria Parasite in Mice

By BiotechDaily International staff writers
Posted on 20 Mar 2012
Chemical modification of the bone-resorption bisphosphonate drugs zoledronate and risedronate enables effective targeting of the elusive intraerythrocytic form of the malaria parasite Plasmodium falciparum.

The modification enables the drugs to cross the cell membrane and thereby readily enter the infected red blood cells (RBCs). Here they act as potent inhibitors of a key enzyme, geranylgeranyl diphosphate synthase (GGPPS), in isoprenoid biosynthesis, an essential survival and defense pathway for the parasite. The drugs have little effect on this pathway in human or mouse cells.

Scientists identified the modified drugs with an in vitro assay targeting the RBC form of P. falciparum in screening a library of several hundred drug compounds known to be isoprenoid biosynthesis inhibitors. Based on "growth-rescue" and enzyme-inhibition experiments, GGPPS was shown to be a major target for the most potent leads, labeled BPH-703 and BPH-811, lipophilic analogs of zoledronate and risedronate.

“We found that compounds that were really active had a very long hydrocarbon chain. These compounds can cross the cell membrane and work at very low concentrations,” said Eric Oldfield, PhD and professor of chemistry at the University of Illinois at Urbana-Champaign (UIUC; IL, USA). Compared to the parent compounds, the lipophilic analogs show enhanced binding to the target GGPPS enzyme and only the lipophilic species are active in cells.

In vivo, the drugs were effective against Plasmodium with no observed toxicity to the mice – BPH-703 and BPH-811 tested in mice both resulted in major decreases in parasitemia and 100% mouse survival.

“It’s important to find new drug targets because malaria drugs last only a few years, maybe 10 years, before you start to get resistance,” Oldfield said. Study coauthor Yonghui Zhang, research scientist in Prof. Oldfield’s lab, noted, “We are the first to show that the enzyme GGPPS is a valid target for malaria."

The study appears in the March 5, 2012, edition of the journal Proceedings of the National Academy of Sciences USA. These results are also of broader interest as they indicate that it may be possible to overcome barriers to cell penetration of existing bisphosphonate drugs in this and other systems by simple covalent modification to form lipophilic analogs that retain their enzyme-inhibition activity and are also effective in vitro and in vivo.

Related Links:
University of Illinois at Urbana-Champaign




Channels

Genomics/Proteomics

view channel
Image: The TheraCyte cell encapsulation device (Photo courtesy of TheraCyte, Inc.).

Encapsulated Human-Insulin-Producing Progenitor Cells Cure Diabetes in Mouse Model

A breakthrough system that allows subcutaneous implantation of encapsulated immature pancreatic cells (beta progenitor cells) was shown to produce enough insulin to correct the symptoms of diabetes in a mouse model.... Read more

Biochemistry

view channel

Mitochondrial Cause of Aging Can Be Reversed

Researchers have found a cause of aging in lab animals that can be reversed, possibly providing an avenue for new treatments for age-related diseases including type 2 diabetes, cancer, muscle wasting, and inflammatory diseases. The researchers plan to begin human trials late 2014. The study, which was published December... Read more

Therapeutics

view channel

Cytokine Identified That Causes Mucositis in Cancer Therapy Patients

The action of the cytokine interleukin 1-beta (IL-1beta) has been found to underlie the onset of mucositis, a common, severe side effect of chemotherapy and irradiation of cancer patients. Mucositis occurs as a result of cell death in reaction to chemo- or radiotherapy. The mucosal lining of the mouth becomes thin, may... Read more

Business

view channel

Analytical Sciences Trade Fair Declared a Rousing Success

Organizers of this year's 24th "analytica" biosciences trade fair have reported significant increases in both the number of visitors and exhibitors compared to the 2012 event. The analytica trade fair for laboratory technology, analysis, and biotechnology has been held at the Munich (Germany) Trade Fair Center every... Read more
 
Copyright © 2000-2014 Globetech Media. All rights reserved.