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Malaria kills over 600,000 people a year, and as the climate warms, the potential range of the disease is growing. While some drugs can effectively prevent and treat malaria, resistance to those drugs is also on the rise.
New research from 麻豆学生精品版 has identified a promising target for new antimalarial drugs: a protein called DMT1, which allows single-celled malaria parasites to use iron, which is critical for parasites to survive and reproduce.
The results suggest that medications that block DMT1 might be very effective against malaria.
An ironic mystery
associate professor of biochemistry in the Spencer Fox Eccles School of Medicine (SFESOM) at the University of Utah, knew that iron is essential for parasite survival. Without iron, parasites rapidly die. And getting that iron from the human red blood cells in which the parasites live and divide is no simple task.
鈥淲e still don't really understand how parasites acquire iron in the red blood cell, which is rather ironic given that it's the most iron rich cell in the human body,鈥 says Sigala, who is the senior author on the paper.
Researchers knew that the malaria parasites had to harvest iron-rich hemoglobin from human blood cells, crack it open to get at the iron inside, and move the iron to the parts of the parasite that need it.
But the proteins involved were 鈥渁 bit of a black hole,鈥 says a graduate researcher in biochemistry in SFESOM and the first author on the paper. Malaria parasites are so distinct from better-studied organisms that the scientists had little prior knowledge to go on. 鈥淭hey don't have a lot of the normal proteins that you would need to get iron and transport it.鈥
A key player
The researchers suspected that DMT1 might help malaria parasites use iron because it looks somewhat similar to genes involved in metal transport in other organisms.
Importantly, they found that DMT1 is absolutely critical for parasite survival. The researchers edited the malaria parasites鈥 genome so that they could turn off DMT1 protein production at will. When they turned DMT1 off, the parasites died before being able to infect more blood cells鈥攁n unusually rapid demise, even for the loss of an essential protein.
The parasites鈥 rapid death could be a consequence of the importance of iron transport in many processes, Sigala says. 鈥淏locking [this protein] is expected to impair not just one or two key processes but nearly all aspects of parasite viability during blood-stage infection,鈥 he says.
Sure enough, DMT1 is necessary specifically because it鈥檚 involved in iron transport, the team confirmed. When they turned DMT1 activity down but not totally off鈥攍ike a light on a dimmer switch鈥攖he parasites could still survive, but their growth slowed down. Intriguingly, giving them lots of extra iron brought them back up to speed. The researchers believe that, when iron is abundant in the environment, the handful of remaining DMT1 proteins can transport it quickly enough for parasites to grow normally. When there鈥檚 no DMT1 whatsoever, it doesn鈥檛 matter how much iron is around鈥攎alaria parasites can鈥檛 use it and rapidly die.
A crack in the door
The researchers are hopeful that DMT1 could be an effective target for new antimalarial drugs, thanks to its moderate similarity to human iron transporters, Loveridge says. 鈥淚t鈥檚 similar enough that we could identify it,鈥 he says, 鈥渂ut different enough that it鈥檚 possible that you could design a parasite-specific inhibitor of this transporter that has minimal impacts on the human protein.鈥
The fact that the parasites die so quickly when DMT1 is turned off is promising; if a drug can be developed or identified that prevents DMT1 activity, it could be faster-acting than current options. The lab is currently testing existing iron transport inhibitors to see if they could work as antimalarial drugs.
Loveridge adds that whether or not their discovery leads to new drug development, it鈥檒l make it easier for future scientists to uncover more information about how the parasite grows and how to stop it. 鈥淲e鈥檙e kind of cracking the door,鈥 he says. 鈥淚 hope that other people can throw it wide open.鈥
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These results were published as in PNAS on October 28, 2024.
This research was supported by NIH grants R35GM133764 and T32TR004392, the Utah Center for Iron and Heme Disorders, and the American Heart Association.