Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

New therapeutic approach to combat African sleeping sickness

20.02.2019

Small inhibitor molecule inhibits parasitic enzyme / Novel concept could also be employed in the future rational design of drugs for the treatment of other diseases

Scientists working in a range of disciplines joined forces to identify a new approach to combat African sleeping sickness. Fundamental research undertaken under the supervision of Professor Ute Hellmich of Johannes Gutenberg University Mainz (JGU) has revealed a promising strategy to develop a suitable agent.


Trypanosomes, which cause African sleeping sickness, under the microscope (left) and the crystal structure of the tryparedoxin dimer (right): The two inhibitor molecules are highlighted in red.

Ill./©: Ute Hellmich, Annika Wagner

"There is still a long way to go before we arrive at a pharmaceutical product," said Hellmich. "But our highly interdisciplinary work involving parasitology, theoretical and organic chemistry, structural biology, and biochemistry has shown how the parasite that causes sleeping sickness can be rendered harmless."

The researchers succeeded in demonstrating how a specific inhibitory substance docks on to and deactivates a vital protein of the parasite.

African sleeping sickness is caused by trypanosomes, unicellular protozoans transmitted by the bite of an infected tsetse fly. According to the World Health Organization, the number of infected people has declined in recent years, down to an estimated 15,000 in 2014.

However, establishing the actual incidence of the disease is difficult, as the early symptoms are similar to those of malaria. "Not only the poorest people in sub-Saharan Africa are threatened, but also their cattle, which are affected on a dramatic scale by certain species of Trypanosoma brucei," explained biochemist Professor Ute Hellmich.

Currently, only a handful of drugs to treat sleeping sickness, which is fatal if left untreated, are available and these treatments are often accompanied by severe side effects and even fatalities in up to 10 percent of patients. Although new drugs are currently being developed, the approach of Hellmich's group goes one step further:

"Our inhibitor opens up the future prospect of being able to design inhibitors on a fundamental level and could thus possibly also be used in the treatment of infection with other, related pathogenic parasites, such as Leishmania," Annika Wagner, lead author of the study recently published in Angewandte Chemie International Edition, pointed out.

Inhibitor induces dimerization of essential parasite protein

The principle is based on the fact that a small, selective inhibitor binds to the enzyme tryparedoxin. This protein is essential for the parasite, protecting it from oxidative damage, but is not present in humans, making it a viable drug target.

To their surprise, the team of researchers discovered that when the inhibitor binds to the protein, two of the resulting inhibitor-protein complexes then combine to form a stable dimer. When this occurs, the usually monomeric protein ceases to function.

"We were astonished and initially thought it was a chance effect due to experimental conditions," said Hellmich. The investigation was then extended, and it was verified in a large-scale study using various methods that the dimerization effect could be reproduced.

In addition to the Mainz research teams of Professor Ute Hellmich and Professor Till Opatz, researchers from the universities of Frankfurt, Würzburg, Heidelberg, and the European Molecular Biology Laboratory (EMBL) in Grenoble were involved.

Highly interdisciplinary research proves successful

The dimerization that the research has uncovered is unusual because the molecule responsible is extremely small. Most molecules that act like a molecular adhesive to combine individual monomers to form a dimer are relatively large. "Our molecule is much smaller and able to directly recognize the protein," explained Hellmich. Small molecules are also easier to smuggle into cells, which might be the starting point for new drug concepts.

By precisely demonstrating the mechanism by which the parasite protein is chemically inhibited and dimerized by the small molecule, the interdisciplinary research partnership has staked out the fundamentals underlying such a new concept.

"It was crucial that we didn't stop at our original goal of merely determining the crystal structure of the protein-inhibitor complex," said Hellmich. "Instead, we took a second look at the result and then discussed it with experts from different fields. Research only progresses when we work together."

Image:
http://www.uni-mainz.de/bilder_presse/09_biochemie_schlafkrankheit.jpg
Trypanosomes, which cause African sleeping sickness, under the microscope (left) and the crystal structure of the tryparedoxin dimer (right): The two inhibitor molecules are highlighted in red.
Ill./©: Ute Hellmich, Annika Wagner

Wissenschaftliche Ansprechpartner:

Junior Professor Dr. Ute Hellmich
Membrane Biochemistry
Institute of Pharmaceutical Sciences and Biochemistry – Therapeutic Life Sciences
Johannes Gutenberg University Mainz
55099 Mainz, GERMANY
phone +49 6131 39-26182
fax +49 6131 39-25348
e-mail: u.hellmich@uni-mainz.de
https://www.blogs.uni-mainz.de/fb09hellmich/jun-prof-dr-ute-a-hellmich/

Originalpublikation:

A. Wagner et al., Inhibitor‐induced dimerization of an essential oxidoreductase from African trypanosomes, Angewandte Chemie International Edition, 3 January 2019,
DOI:10.1002/anie.201810470
https://onlinelibrary.wiley.com/doi/full/10.1002/anie.201810470

Weitere Informationen:

https://www.blogs.uni-mainz.de/fb09hellmich/membrane-biochemistry/ – Hellmich Group on Membrane Biochemistry at Mainz University

Petra Giegerich | idw - Informationsdienst Wissenschaft

More articles from Life Sciences:

nachricht To proliferate or not to proliferate
21.03.2019 | Max-Planck-Institut für molekulare Zellbiologie und Genetik

nachricht Discovery of a Primordial Metabolism in Microbes
21.03.2019 | Leibniz-Institut DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Magnetic micro-boats

Nano- and microtechnology are promising candidates not only for medical applications such as drug delivery but also for the creation of little robots or flexible integrated sensors. Scientists from the Max Planck Institute for Polymer Research (MPI-P) have created magnetic microparticles, with a newly developed method, that could pave the way for building micro-motors or guiding drugs in the human body to a target, like a tumor. The preparation of such structures as well as their remote-control can be regulated using magnetic fields and therefore can find application in an array of domains.

The magnetic properties of a material control how this material responds to the presence of a magnetic field. Iron oxide is the main component of rust but also...

Im Focus: Self-healing coating made of corn starch makes small scratches disappear through heat

Due to the special arrangement of its molecules, a new coating made of corn starch is able to repair small scratches by itself through heat: The cross-linking via ring-shaped molecules makes the material mobile, so that it compensates for the scratches and these disappear again.

Superficial micro-scratches on the car body or on other high-gloss surfaces are harmless, but annoying. Especially in the luxury segment such surfaces are...

Im Focus: Stellar cartography

The Potsdam Echelle Polarimetric and Spectroscopic Instrument (PEPSI) at the Large Binocular Telescope (LBT) in Arizona released its first image of the surface magnetic field of another star. In a paper in the European journal Astronomy & Astrophysics, the PEPSI team presents a Zeeman- Doppler-Image of the surface of the magnetically active star II Pegasi.

A special technique allows astronomers to resolve the surfaces of faraway stars. Those are otherwise only seen as point sources, even in the largest telescopes...

Im Focus: Heading towards a tsunami of light

Researchers at Chalmers University of Technology and the University of Gothenburg, Sweden, have proposed a way to create a completely new source of radiation. Ultra-intense light pulses consist of the motion of a single wave and can be described as a tsunami of light. The strong wave can be used to study interactions between matter and light in a unique way. Their research is now published in the scientific journal Physical Review Letters.

"This source of radiation lets us look at reality through a new angle - it is like twisting a mirror and discovering something completely different," says...

Im Focus: Revealing the secret of the vacuum for the first time

New research group at the University of Jena combines theory and experiment to demonstrate for the first time certain physical processes in a quantum vacuum

For most people, a vacuum is an empty space. Quantum physics, on the other hand, assumes that even in this lowest-energy state, particles and antiparticles...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

International Modelica Conference with 330 visitors from 21 countries at OTH Regensburg

11.03.2019 | Event News

Selection Completed: 580 Young Scientists from 88 Countries at the Lindau Nobel Laureate Meeting

01.03.2019 | Event News

LightMAT 2019 – 3rd International Conference on Light Materials – Science and Technology

28.02.2019 | Event News

 
Latest News

To proliferate or not to proliferate

21.03.2019 | Life Sciences

Magnetic micro-boats

21.03.2019 | Physics and Astronomy

Motorless pumps and self-regulating valves made from ultrathin film

21.03.2019 | HANNOVER MESSE

VideoLinks
Science & Research
Overview of more VideoLinks >>>