Features | Partner Sites | Information | LinkXpress
Sign In
GLOBETECH MEDIA
GLOBETECH PUBLISHING LLC
GLOBETECH PUBLISHING LLC

Imidazopyrazines Kill the Malaria Parasite at Every Stage of Its Life Cycle

By BiotechDaily International staff writers
Posted on 09 Dec 2013
Image: Malaria parasites (labeled with fluorescent protein) in the late stages of development, superimposed on a field of red blood cells. The many nuclei of the parasites\' daughter cells are labeled in blue, and the plasma membranes surrounding the daughter cells are labeled in green. Imidazopyrazine treatment disrupts formation of the membranes around the daughter cells (Photo courtesy of Dr. Marcus C.S. Lee, Columbia University Medical Center).
Image: Malaria parasites (labeled with fluorescent protein) in the late stages of development, superimposed on a field of red blood cells. The many nuclei of the parasites\' daughter cells are labeled in blue, and the plasma membranes surrounding the daughter cells are labeled in green. Imidazopyrazine treatment disrupts formation of the membranes around the daughter cells (Photo courtesy of Dr. Marcus C.S. Lee, Columbia University Medical Center).
An enzyme that is vital to all life stages of several species of malaria parasites has been cited as a tempting target for drug developers.

Achieving the goal of malaria elimination will depend on targeting pathways essential across all life stages of the parasite, Plasmodium. Towards this end, investigators at Columbia University Medical Center (New York, NY, USA) collaborated with an international team of researchers to screen more than a million drug compounds against the most lethal malaria parasite, Plasmodium falciparum, in order to identify compounds capable of killing the parasite at each stage of its life cycle.

They reported in the November 27, 2013, online edition of the journal Nature that the class of compounds called imidazopyrazines was capable of inhibiting the intracellular development of P. falciparum and several other species including P. vivax and P. cynomolgi at every stage of infection in the vertebrate host.

Imidazopyrazines demonstrated potent preventive, therapeutic, and transmission-blocking activity in rodent malaria models and were active against blood-stage field isolates of the major human pathogens P. falciparum and P. vivax. In addition, they inhibited liver-stage hypnozoites in the simian parasite P. cynomolgi.

The target of imidazopyrazine inhibition was found to be the enzyme phosphatidylinositol 4-kinase (PI(4)K). Imidazopyrazines altered the intracellular distribution of phosphatidylinositol-4-phosphate in the parasite's Golgi organelle by occupying PI(4)K's ATP-binding pocket.

“We think that disrupting the function of PI(4)K at the Golgi stops the parasite from making new membranes around its daughter cells, thereby preventing the organism from reproducing,” said senior author Dr. Marcus C. S. Lee, associate research scientist in microbiology and immunology at Columbia University Medical Center.

“Perhaps the most exciting aspect of our findings is that this enzyme is required at all stages of the parasites’ life cycle in humans,” said Dr. Lee. “This is important because most antimalarials are effective at killing the parasites only as they circulate in the bloodstream. However, the parasites can hide in the liver for years before reemerging and triggering a relapse of the disease. By identifying this enzyme, we may be able to develop a new way to kill the parasites in their dormant stage.”

Related Links:

Columbia University Medical Center



Channels

Biochemistry

view channel
Image:  Model depiction of a novel cellular mechanism by which regulation of cryptochromes Cry1 and Cry2 enables coordination of a protective transcriptional response to DNA damage caused by genotoxic stress (Photo courtesy of the journal eLife, March 2015, Papp SJ, Huber AL, et al.).

Two Proteins Critical for Circadian Cycles Protect Cells from Mutations

Scientists have discovered that two proteins critical for maintaining healthy day-night cycles also have an unexpected role in DNA repair and protecting cells against genetic mutations that could lead... Read more

Business

view channel

NanoString and MD Anderson Collaborate on Development of Novel Multi-Omic Expression Profiling Assays for Cancer

The University of Texas MD Anderson Cancer Center (Houston, TX, USA) and NanoString Technologies, Inc. (Seattle, WA, USA) will partner on development of a revolutionary new type of assay—simultaneously profiling gene and protein expression, initially aiming to discover and validate biomarker signatures for immuno-oncology... Read more
 
Copyright © 2000-2015 Globetech Media. All rights reserved.