Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

A New Approach to Malaria Treatment?

21.01.2014
Halogenated natural alkaloids show herbicidal and antiplasmodial activity

Two of the most urgent challenges for scientists are the battles against food shortages and infectious diseases like malaria.



Unfortunately, both the herbicides used to protect plants and the anti-infectives that shield us from disease rapidly lose their effectiveness as the target organisms develop resistance.

In order to benefit both fields at once, scientists tested lead compounds from agrochemical research against infectious germs as well. In this way, a team of German and Swiss researchers has found a new candidate that may work against malaria, as they report in the journal Angewandte Chemie.

“Recently, enzymes from the non-mevalonate terpene biosynthetic pathway have been identified as attractive target structures with novel modes of activity for the development of herbicides and drugs against infectious diseases,” explains François Diederich from the ETH Zurich (Switzerland).

“This biosynthetic pathway is found in many human pathogens and in plants, but does not occur in mammals.” Correspondingly, an inhibitor should only have a toxic effect on pathogens and plants, not humans. Diederich and his co-workers at the ETH, TU Munich, BASF-SE, the University of Hamburg, the Swiss Tropical Institute STPHI in Basel, and TU Dresden have now discovered new inhibitors and characterized the ways in which they work.

By using high-throughput screening methods, the researchers of BASF SE led by Matthias Witschel tested about 100,000 compounds for an inhibitory effect against plant IspD, an enzyme of the aforementioned non-mevalonate terpene biosynthetic pathway – and found several hits.

The most interesting compounds are pseudilins, highly halogenated alkaloids from marine bacteria, and have a significant inhibitory effect on IspD, as researchers at the TU Munich led by Michael Groll demonstrated in NMR-based tests and researchers at the University of Hamburg led by Markus Fischer showed in photometric tests. Says Groll: “Interestingly, the chemical scaffold of the pseudilins is completely different from that of a previously discovered IdpD inhibitor. This suggests that the mode of action should also be different.”

To research this mechanism, Andrea Kunfermann from Groll’s team synthesized cocrystals of the pseudilins and IspD enzymes and examined them by X-ray crystallography. This showed that the pseudilins bind to an allosteric pocket in the enzyme. Halogen atoms in the pseudilins build up halogen bridges to the enzyme, which are, in addition to metal ion coordination, responsible for the strong binding. Occupation of this pocket changes the shape of the enzyme so that a cosubstrate required for proper functioning of the enzyme can no longer dock at the binding site in the active center.

“The pseudilins demonstrated herbicidal activity in plant assays and were active against Plasmodium falciparum, the pathogen that causes Malaria tropica and is dependent on the non-mevalonate biosynthesis pathway for survival,” reports Diederich. The researchers hope to use this as a new starting point for malaria treatment.

About the Author
François Diederich is a professor at ETH Zürich, Michael Groll is a professor at TU München, Markus Fischer is a professor at the University of Hamburg, and Matthias Witschel is a scientist at BASF SE working in the field of crop protection.
Author: François Diederich, ETH Zürich (Switzerland), http://www.diederich.chem.ethz.ch/
Title: Pseudilins: Halogenated, Allosteric Inhibitors of the Non-Mevalonate Pathway Enzyme IspD

Angewandte Chemie International Edition, Permalink to the article: http://dx.doi.org/10.1002/anie.201309557

François Diederich | Angewandte Chemie
Further information:
http://pressroom.angewandte.org
http://www.diederich.chem.ethz.ch/

More articles from Life Sciences:

nachricht Ageless ears? Elderly barn owls do not become hard of hearing
26.09.2017 | Carl von Ossietzky-Universität Oldenburg

nachricht eTRANSAFE – collaborative research project aimed at improving safety in drug development process
26.09.2017 | Fraunhofer-Gesellschaft

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: The fastest light-driven current source

Controlling electronic current is essential to modern electronics, as data and signals are transferred by streams of electrons which are controlled at high speed. Demands on transmission speeds are also increasing as technology develops. Scientists from the Chair of Laser Physics and the Chair of Applied Physics at Friedrich-Alexander-Universität Erlangen-Nürnberg (FAU) have succeeded in switching on a current with a desired direction in graphene using a single laser pulse within a femtosecond ¬¬ – a femtosecond corresponds to the millionth part of a billionth of a second. This is more than a thousand times faster compared to the most efficient transistors today.

Graphene is up to the job

Im Focus: LaserTAB: More efficient and precise contacts thanks to human-robot collaboration

At the productronica trade fair in Munich this November, the Fraunhofer Institute for Laser Technology ILT will be presenting Laser-Based Tape-Automated Bonding, LaserTAB for short. The experts from Aachen will be demonstrating how new battery cells and power electronics can be micro-welded more efficiently and precisely than ever before thanks to new optics and robot support.

Fraunhofer ILT from Aachen relies on a clever combination of robotics and a laser scanner with new optics as well as process monitoring, which it has developed...

Im Focus: The pyrenoid is a carbon-fixing liquid droplet

Plants and algae use the enzyme Rubisco to fix carbon dioxide, removing it from the atmosphere and converting it into biomass. Algae have figured out a way to increase the efficiency of carbon fixation. They gather most of their Rubisco into a ball-shaped microcompartment called the pyrenoid, which they flood with a high local concentration of carbon dioxide. A team of scientists at Princeton University, the Carnegie Institution for Science, Stanford University and the Max Plank Institute of Biochemistry have unravelled the mysteries of how the pyrenoid is assembled. These insights can help to engineer crops that remove more carbon dioxide from the atmosphere while producing more food.

A warming planet

Im Focus: Highly precise wiring in the Cerebral Cortex

Our brains house extremely complex neuronal circuits, whose detailed structures are still largely unknown. This is especially true for the so-called cerebral cortex of mammals, where among other things vision, thoughts or spatial orientation are being computed. Here the rules by which nerve cells are connected to each other are only partly understood. A team of scientists around Moritz Helmstaedter at the Frankfiurt Max Planck Institute for Brain Research and Helene Schmidt (Humboldt University in Berlin) have now discovered a surprisingly precise nerve cell connectivity pattern in the part of the cerebral cortex that is responsible for orienting the individual animal or human in space.

The researchers report online in Nature (Schmidt et al., 2017. Axonal synapse sorting in medial entorhinal cortex, DOI: 10.1038/nature24005) that synapses in...

Im Focus: Tiny lasers from a gallery of whispers

New technique promises tunable laser devices

Whispering gallery mode (WGM) resonators are used to make tiny micro-lasers, sensors, switches, routers and other devices. These tiny structures rely on a...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

“Lasers in Composites Symposium” in Aachen – from Science to Application

19.09.2017 | Event News

I-ESA 2018 – Call for Papers

12.09.2017 | Event News

EMBO at Basel Life, a new conference on current and emerging life science research

06.09.2017 | Event News

 
Latest News

Goodbye, login. Hello, heart scan

26.09.2017 | Information Technology

The material that obscures supermassive black holes

26.09.2017 | Physics and Astronomy

Ageless ears? Elderly barn owls do not become hard of hearing

26.09.2017 | Life Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>