Molecular understanding of drug interactions suggests pathway to better malaria treatments

January 15, 2020

The process of crystallization is central to drug development, petrochemical processing and other industrial actions, but scientists say they still are learning about the complex interactions involved in the building and dissolution of crystals.

Researchers from the University of Houston and the Université libre de Bruxelles reported in the journal Nature that they have for the first time demonstrated at the molecular level what happens when two compounds known to inhibit crystal growth - in this case, antimalarial drugs - were combined. The results were unexpected.

"You would expect using two drugs that attacked crystallization in two different ways would be synergistic, or at the very least additive," said Jeffrey Rimer, Abraham E. Dukler Professor of Chemical and Biomolecular Engineering at UH and a co-author of the paper. "Instead, we found that they can work against each other."

Working against each other, known as antagonistic cooperation, meant that the drugs were actually less effective in tandem than individually. Peter Vekilov, John and Rebecca Moores Professor of Chemical and Biomolecular Engineering and Chemistry at UH and another co-author, said the work will allow the design of more effective treatments for malaria, a mosquito-borne disease that killed 435,000 people in 2017, most of them children in Africa.

But more broadly, it suggests a new way to screen molecules for their potential in drug development, allowing new treatments to be developed more quickly.

"When you are using modifiers, a small change in the molecule's structure can dramatically alter its performance," Rimer said.

Malaria is caused by a parasite, which consumes hemoglobin and leaves behind a compound known as hematin, which the parasite sequesters inside a crystal. Antimalarial treatments work by inhibiting the crystal growth, freeing hematin to attack the parasite.

For this work, the researchers studied the growth of hematin crystals in the presence of four antimalarial drugs - chloroquine, quinine, mefloquine and amodiaquine - which work in one of two distinct ways.

Both computationally and experimentally, including through the use of atomic force microscopy, the researchers demonstrated how compounds which attack crystallization by two different mechanisms behave when combined. The resulting molecular-level understanding of that behavior suggests a new mechanism for materials science, Vekilov said.

"This mechanism may provide guidance in the search for suitable inhibitor combinations to control crystallization of pathological, biomimetic, and synthetic materials," the researchers wrote. "In a broader context, our results highlight modifier interactions mediated by the dynamics and structures on the crystal interface as a prime element of the regulation of the shapes and patterns of crystalline structures in nature and industry."
-end-
In addition to Vekilov and Rimer, researchers involved with the project include UH Ph.D. student Wenchuan Ma and collaborator Dr. James Lutsko of the Université libre de Bruxelles.

University of Houston

Related Malaria Articles from Brightsurf:

Clocking in with malaria parasites
Discovery of a malaria parasite's internal clock could lead to new treatment strategies.

Breakthrough in malaria research
An international scientific consortium led by the cell biologists Volker Heussler from the University of Bern and Oliver Billker from the UmeƄ University in Sweden has for the first time systematically investigated the genome of the malaria parasite Plasmodium throughout its life cycle in a large-scale experiment.

Scientists close in on malaria vaccine
Scientists have taken another big step forward towards developing a vaccine that's effective against the most severe forms of malaria.

New tool in fight against malaria
Modifying a class of molecules originally developed to treat the skin disease psoriasis could lead to a new malaria drug that is effective against malaria parasites resistant to currently available drugs.

Malaria expert warns of need for malaria drug to treat severe cases in US
The US each year sees more than 1,500 cases of malaria, and currently there is limited access to an intravenously administered (IV) drug needed for the more serious cases.

Monkey malaria breakthrough offers cure for relapsing malaria
A breakthrough in monkey malaria research by two University of Otago scientists could help scientists diagnose and treat a relapsing form of human malaria.

Getting to zero malaria cases in zanzibar
New research led by the Johns Hopkins Center for Communication Programs, Ifakara Health Institute and the Zanzibar Malaria Elimination Program suggests that a better understanding of human behavior at night -- when malaria mosquitoes are biting -- could be key to preventing lingering cases.

Widely used malaria treatment to prevent malaria in pregnant women
A global team of researchers, led by a research team at the Liverpool School of Tropical Medicine (LSTM), are calling for a review of drug-based strategies used to prevent malaria infections in pregnant women, in areas where there is widespread resistance to existing antimalarial medicines.

Protection against Malaria: A matter of balance
A balanced production of pro and anti-inflammatory cytokines at two years of age protects against clinical malaria in early childhood, according to a study led by ISGlobal, an institution supported by ''la Caixa'' Foundation.

The math of malaria
A new mathematical model for malaria shows how competition between parasite strains within a human host reduces the odds of drug resistance developing in a high-transmission setting.

Read More: Malaria News and Malaria Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.