Featured Research

from universities, journals, and other organizations

Toward a better drug against malaria

Date:
June 5, 2014
Source:
Albert-Ludwigs-Universität Freiburg
Summary:
Structural biologists explain on the molecular level, how the drug atovaquone acts on the pathogen of malaria. 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.

Molecule in a pocket: The illustration shows how atovaquone binds to its target protein.
Credit: Graphic: 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 mitochondrial protein 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 target protein, 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.


Story Source:

The above story is based on materials provided by Albert-Ludwigs-Universität Freiburg. Note: Materials may be edited for content and length.


Journal Reference:

  1. Dominic Birth, Wei-Chun Kao, Carola Hunte. Structural analysis of atovaquone-inhibited cytochrome bc1 complex reveals the molecular basis of antimalarial drug action. Nature Communications, 2014; 5 DOI: 10.1038/ncomms5029

Cite This Page:

Albert-Ludwigs-Universität Freiburg. "Toward a better drug against malaria." ScienceDaily. ScienceDaily, 5 June 2014. <www.sciencedaily.com/releases/2014/06/140605113607.htm>.
Albert-Ludwigs-Universität Freiburg. (2014, June 5). Toward a better drug against malaria. ScienceDaily. Retrieved July 31, 2014 from www.sciencedaily.com/releases/2014/06/140605113607.htm
Albert-Ludwigs-Universität Freiburg. "Toward a better drug against malaria." ScienceDaily. www.sciencedaily.com/releases/2014/06/140605113607.htm (accessed July 31, 2014).

Share This




More Plants & Animals News

Thursday, July 31, 2014

Featured Research

from universities, journals, and other organizations


Featured Videos

from AP, Reuters, AFP, and other news services

Visitors Feel Part of the Pack at Wolf Preserve

Visitors Feel Part of the Pack at Wolf Preserve

AP (July 31, 2014) — Seacrest Wolf Preserve on the northern Florida panhandle allows more than 10,000 visitors each year to get up close and personal with Arctic and British Columbian Wolves. (July 31) Video provided by AP
Powered by NewsLook.com
Florida Panther Rebound Upsets Ranchers

Florida Panther Rebound Upsets Ranchers

AP (July 31, 2014) — With Florida's panther population rebounding, some ranchers complain the protected predators are once again killing their calves. (July 31) Video provided by AP
Powered by NewsLook.com
Dangerous Bacteria Kills One in Florida

Dangerous Bacteria Kills One in Florida

AP (July 31, 2014) — Sarasota County, Florida health officials have issued a warning against eating raw oysters and exposing open wounds to coastal and inland waters after a dangerous bacteria killed one person and made another sick. (July 31) Video provided by AP
Powered by NewsLook.com
Raw: Thousands Flocking to German Crop Circle

Raw: Thousands Flocking to German Crop Circle

AP (July 30, 2014) — Thousands of people are trekking to a Bavarian farmer's field to check out a mysterious set of crop circles. (July 30) Video provided by AP
Powered by NewsLook.com

Search ScienceDaily

Number of stories in archives: 140,361

Find with keyword(s):
 
Enter a keyword or phrase to search ScienceDaily for related topics and research stories.

Save/Print:
Share:  

Breaking News:
from the past week

In Other News

... from NewsDaily.com

Science News

Health News

    Environment News

    Technology News



      Save/Print:
      Share:  

      Free Subscriptions


      Get the latest science news with ScienceDaily's free email newsletters, updated daily and weekly. Or view hourly updated newsfeeds in your RSS reader:

      Get Social & Mobile


      Keep up to date with the latest news from ScienceDaily via social networks and mobile apps:

      Have Feedback?


      Tell us what you think of ScienceDaily -- we welcome both positive and negative comments. Have any problems using the site? Questions?
      Mobile iPhone Android Web
      Follow Facebook Twitter Google+
      Subscribe RSS Feeds Email Newsletters
      Latest Headlines Health & Medicine Mind & Brain Space & Time Matter & Energy Computers & Math Plants & Animals Earth & Climate Fossils & Ruins