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 Identifying drug targets for leukaemia
02.05.2016 | The Hong Kong Polytechnic University

nachricht A cell senses its own curves: New research from the MBL Whitman Center
29.04.2016 | Marine Biological Laboratory

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: 2+1 is Not Always 3 - In the microworld unity is not always strength

If a person pushes a broken-down car alone, there is a certain effect. If another person helps, the result is the sum of their efforts. If two micro-particles are pushing another microparticle, however, the resulting effect may not necessarily be the sum their efforts. A recent study published in Nature Communications, measured this odd effect that scientists call “many body.”

In the microscopic world, where the modern miniaturized machines at the new frontiers of technology operate, as long as we are in the presence of two...

Im Focus: Tiny microbots that can clean up water

Researchers from the Max Planck Institute Stuttgart have developed self-propelled tiny ‘microbots’ that can remove lead or organic pollution from contaminated water.

Working with colleagues in Barcelona and Singapore, Samuel Sánchez’s group used graphene oxide to make their microscale motors, which are able to adsorb lead...

Im Focus: ORNL researchers discover new state of water molecule

Neutron scattering and computational modeling have revealed unique and unexpected behavior of water molecules under extreme confinement that is unmatched by any known gas, liquid or solid states.

In a paper published in Physical Review Letters, researchers at the Department of Energy's Oak Ridge National Laboratory describe a new tunneling state of...

Im Focus: Bionic Lightweight Design researchers of the Alfred Wegener Institute at Hannover Messe 2016

Honeycomb structures as the basic building block for industrial applications presented using holo pyramid

Researchers of the Alfred Wegener Institute (AWI) will introduce their latest developments in the field of bionic lightweight design at Hannover Messe from 25...

Im Focus: New world record for fullerene-free polymer solar cells

Polymer solar cells can be even cheaper and more reliable thanks to a breakthrough by scientists at Linköping University and the Chinese Academy of Sciences (CAS). This work is about avoiding costly and unstable fullerenes.

Polymer solar cells can be even cheaper and more reliable thanks to a breakthrough by scientists at Linköping University and the Chinese Academy of Sciences...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

The “AC21 International Forum 2016” is About to Begin

27.04.2016 | Event News

Soft switching combines efficiency and improved electro-magnetic compatibility

15.04.2016 | Event News

Grid-Supportive Buildings Give Boost to Renewable Energy Integration

12.04.2016 | Event News

 
Latest News

Identifying drug targets for leukaemia

02.05.2016 | Life Sciences

Clay nanotube-biopolymer composite scaffolds for tissue engineering

02.05.2016 | Materials Sciences

NASA's Fermi Telescope helps link cosmic neutrino to blazar blast

02.05.2016 | Physics and Astronomy

VideoLinks
B2B-VideoLinks
More VideoLinks >>>