Modified Osteoporosis Drugs Kill Malaria Parasite in Mice

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