Toward a better drug against malaria

Toward a better drug against malaria
Molecule in a pocket: The illustration shows how atovaquone binds to its target protein. Credit: Dominic Birth, Carola Hunte

A research team led by Prof. Dr. Carola Hunte has succeeded in describing how the antimalarial drug atovaquone binds to its target protein. The scientists used x-ray crystallography to determine the three-dimensional structure of the protein with the active substance bound. The drug combination atovaquone-proguanil (Malarone) is a medication used worldwide for the prevention and treatment of malaria. The data and the resulting findings concerning the mode of action of atovaquone could lead to improved medications against the tropical disease. Hunte and her team conducted the research at the Institute for Biochemistry and Molecular Biology of the Faculty of Medicine and the Centre for Biological Signalling Studies BIOSS at the University of Freiburg. The scientists published their findings in the journal Nature Communications.

Malaria is one of the most dangerous tropical diseases in the world. Anopheles mosquitoes infected with Plasmodium species - unicellular parasites - transmit the disease by biting. Atovaquone blocks a protein of the respiratory chain in the mitochondria, the power plants of the cell, thus killing off the parasites. However, the pathogen is susceptible to mutations so that drug resistant strains are arising and spreading. The Freiburg scientists have now paved the way for the development of improved drugs by revealing the precise binding mode of atovaquone to the target protein. They used the from cells of baker's yeast for their analyses due to its close resemblance to the parasitic protein.

The target protein of atovaquone is the third of four enzymes of the respiratory chain in the mitochondrion. The amino acid chains of the protein form a three-dimensional pocket. The molecule of the active substance fits perfectly into this pocket, binding to amino acids at numerous positions. These interactions are crucial for the effect atovaquone has in Plasmodium cells, ultimately leading to the death of the pathogen. The researchers conducted a protein sequence analysis, revealing that most of these docking sites are identical in the pathogen, baker's yeast and in human cells. Atovaquone forms several bonds that are specific to the Plasmodium protein in the open area of the binding pocket. In addition, the structural analysis revealed the molecular basis of resistances: Due to mutations that change the structure of the , the substance cannot reach the designated binding mode - it doesn't fit perfectly into the pocket anymore.

The data provides an important basis for improving antimalarial drugs. Scientists could now modify the molecular structure of atovaquone by means of structure-based drug design, ensuring that the active substance forms necessary bonds - and that the pathogen is no longer resistant to it.

More information: Birth, D., Kao, W.-C., & Hunte, C. (2014). Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action. Nat Commun, 5., dx.doi.org/10.1038/ncomms5029

add to favorites email to friend print save as pdf

Related Stories

Focus on biological signalling to defeat malaria

Jun 06, 2014

Millions of people die each year of malaria – a disease transmitted by the Anopheles mosquito. There are major barriers in vaccine development as well as increased resistance to currently available therapies. New biological ...

New discovery could lead to powerful new anti-malaria drugs

Mar 20, 2013

An international study has discovered a molecule which could form the basis of powerful new anti-malaria drugs. The paper "Quinolone-3-Diarylethers: a new class of drugs for a new era of malaria eradication" has been published ...

A tailor made molecule against malaria

Mar 12, 2014

The malaria parasite is particularly pernicious since it is built to develop resistance to treatments. The lack of new therapeutic approaches also contributes to the persistence of this global scourge. A ...

Scientists crack riddle of important drug target

Dec 02, 2013

A new approach to mapping how proteins interact with each other, developed at the Salk Institute for Biological Studies, could aid in the design of new drugs for diseases such as diabetes and osteoporosis. By reengineering ...

Recommended for you

Xtoro approved for swimmer's ear

12 hours ago

(HealthDay)—Xtoro (finafloxacin otic suspension) eardrops have been approved by the U.S. Food and Drug Administration to treat swimmer's ear, clinically known as acute otitis externa.

Drug interaction identified for ondansetron, tramadol

12 hours ago

(HealthDay)—In the early postoperative period, ondansetron is associated with increased requirements for tramadol consumption, according to a review and meta-analysis published online Dec. 10 in Anaesthesia.

New system targets germs in donated blood plasma

Dec 17, 2014

(HealthDay)—A new system designed to eliminate germs in donated blood plasma and reduce the risk of transmitting a plasma-borne infection has been approved by the U.S. Food and Drug Administration.

Judge halts Alzheimer's drug swap until July

Dec 16, 2014

A federal judge has ordered an Irish drug manufacturer to halt its plans to discontinue its widely used Alzheimer's medication, allegedly in an effort to drive patients to a newer patented drug.

User comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.