Promising Breakthroughs in the Fight Against Malaria
From a "needle in a haystack" search through 2,600 FDA-approved drugs for a new antimalarial, to uncovering the secrets of the Anopheles mosquito's immune system, Malaria Research Institute scientists score victories one discovery at a time.
The allergy medication astemizole may be a promising new treatment for malaria, according to a new study by researchers from the Johns Hopkins Malaria Research Institute (JHMRI) and the School of Medicine In laboratory tests and experiments with mice, the researchers showed that astemizole killed the parasite Plasmodium falciparum, which causes malaria in humans, including strains that were resistant to traditional malaria therapies. The study was published in the August edition of Nature Chemical Biology.
Finding the link between astemizole and malaria was like finding the proverbial needle in a haystack. Four years ago, David Sullivan, MD, an associate professor of Molecular Microbiology and Immunology (MMI), and Curtis Chong, a Hopkins medical student, began developing the Clinical Compound Library. The collection is double the size of the biggest drug libraries with more than 2,687 drugs—nearly half of all FDA-approved medications. Sullivan and Lirong Shi, a JHMRI research technician, tested drugs one by one to see how Plasmodium reacted to them.
Astemizole was sold under the brand name Hismanal for 15 years before it was voluntarily pulled from U.S. and European markets in 1999 after concerns about the drug's safety led to sluggish sales. The drug was reported to cause rare but life-threatening heart arrhythmias when patients took an overdose. Despite rejection of astemizole in some markets, more than 30 countries still use it, including Cambodia, Thailand and Vietnam, where malaria is endemic. And as Sullivan noted, arrhythmia is also a risk with existing malaria drugs and with other antihistamines now sold over the counter.
The next step for Sullivan and his colleagues is to determine if astemizole will be effective in treating people with malaria or if it can be used in combination with existing malaria drugs. The process will be accelerated because the medication has already been approved.
Sullivan's work wasn't the only breakthrough made by JHMRI researchers in recent months. George Dimopoulos, an MMI assistant professor, and his team identified a gene in the Anopheles gambiae mosquito's DNA that is central to the insect's ability to defend against infectious pathogens, including Plasmodium. The AgDscam gene, as it is known, works like a combination lock by creating the right match of adhesion proteins for recognizing and attacking a particular pathogen. The gene's function is in some ways similar to the way human antibodies work, although antibodies use a different process to form adhering proteins.
"The mosquito doesn't need 31,000 genes to make 31,000 receptors. This one gene can produce 31,000 combinations against a variety of pathogens, including Plasmodium, bacteria and fungi," says Dimopoulos, PhD. "It's really a marvel in gene economy. This gene can make 31,000 combinations, which is double the number of genes in the mosquito's entire genome."
The team's findings were published in the June 20 edition of PloS Biology.
In a separate study published in the June 8 issue of PloS Pathogens, Dimopoulos and colleagues found that mosquitoes employed the same immune factors to fight off bacterial pathogens as they do to kill Plasmodium. According to Dimopoulos, the research could point the way toward the development of new malaria-control strategies.
"Potentially, a mosquito with an enhanced capacity to recognize and kill Plasmodium would not transmit malaria. Now we have to figure out how to make the mosquito's immune system more effective in killing malaria parasites," says Dimopoulos.