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"We think this is a very promising target for drug development," says Daniel Goldberg. "We're a long way from getting a new drug, but in the short term we may look at screening a variety of compounds." (Credit: Orin Zebest/Flickr)

drug development

Future drugs could ‘entomb’ malaria parasite

Scientists may be able to “entomb” the malaria parasite, which would keep it from tapping into resources from surrounding cells and cause its death.

As it invades a red blood cell, the malaria parasite takes part of the host cell’s membrane to build a protective compartment. To grow properly, steal nourishment, and dump waste, the parasite then starts a series of major renovations that transform the red blood cell into a suitable home.

But the new research reveals the proteins that make these renovations must pass through a single pore in the parasite’s compartment to get into the red blood cell. When the scientists disrupted passage through that pore in cell cultures, the parasite stopped growing and died.

A malaria-infected red blood cell
Scientists may have found a way to imprison the malaria parasite in its protective chamber inside red blood cells. In the electron micrograph above, the malaria parasites appear in blue and uninfected red blood cells are shown in red. (Credit: NIAID/Flickr)

“The malaria parasite secretes hundreds of diverse proteins to seize control of red blood cells,” says first author Josh R. Beck, a postdoctoral research scholar at Washington University in St. Louis. “We’ve been searching for a single step that all those various proteins have to take to be secreted, and this looks like just such a bottleneck.”

Researchers believe blocking the pore leaves the parasite fatally imprisoned, unable to steal resources from the red blood cell or dispose of its wastes.

The malaria parasite, Plasmodium falciparum, is among the world’s deadliest pathogens. Malaria is spread mainly by the bite of infected mosquitoes and is most common in Africa.

In 2012, an estimated 207 million cases of malaria occurred worldwide, leading to 627,000 deaths, according to the World Health Organization. Resistance to drug treatments is spreading among the parasite’s many strains, and researchers are working hard to find new drug targets.

‘Heat shock’ proteins

Senior author of the paper published in the journal Nature, Daniel Goldberg, professor of medicine and of molecular microbiology and a Howard Hughes Medical Institute investigator at Washington University, studies how malaria affects red blood cells.

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In the new study, he and his colleagues looked at heat shock protein 101 (HSP101). Scientists named this family of proteins “heat shock” because they become active when cells are overheated or stressed. The proteins have multiple functions, including guiding the folding and unfolding of other proteins.

Previous studies have suggested that HSP101 might be involved in protein secretion. The researchers disabled HSP101 in cell cultures, expecting to block the discharge of some malarial proteins. To their surprise, they stopped all of them.

“We think this is a very promising target for drug development,” Goldberg says. “We’re a long way from getting a new drug, but in the short term we may look at screening a variety of compounds to see if they have the potential to block HSP101.”

Folding and a ‘biochemical kick’

The scientists think HSP101 may ready malarial proteins for secretion through a pore that opens into the red blood cell. Part of this preparation may involve unfolding the proteins into a linear form that allows them to more easily pass through the narrow pore. HSP101 may also give the proteins a biochemical kick that pushes them through the pore.

Beck notes that researchers at the Burnet Institute neutralized the parasite in a similar fashion by disabling another protein thought to be involved in the passage of proteins through this pore.

“That suggests there are multiple components of the process that we may be able to target with drugs,” he says. “In addition, many of the proteins involved in secretion are unlike any human proteins, which means we may be able to disable them without adversely affecting important human proteins.”

The National Institutes of Health supported this research.

Source: Washington University in St. Louis

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