Binding at five sites: effective cholera inhibitor based on cholera toxins
Cholera against cholera: a novel inhibitor prevents the cholera toxin from binding to carbohydrates found on the surface of intestinal cells. An international team of researchers has described their elegant concept in the journal Angewandte Chemie:
The protein scaffold of the inhibitor is based on an inactive cholera toxin. It is equipped with five sugar moieties to act as ligands. The inhibitor’s size and number of binding sites are both perfectly matched to the cholera toxin bearing five binding sites.
Cholera is a bacterial infectious disease that is primarily transmitted through insufficiently treated drinking water and contaminated foods. The actual pathogen is a toxin released by the bacteria; it attacks the cells of the intestine and causes life-threatening diarrhea.
Cholera toxin is a protein consisting of a toxic A unit and five nontoxic B units (CTB). Its shape resembles a blossom with five petals. The “petals” are nontoxic, but they bind to special carbohydrates—the oligosaccharide units on glycolipid GM1—on the surface of intestinal cells, initiating uptake of the toxin. Each of the five B subunits possesses a specific binding site for the special sugar motif.
In order to put a stop to the pentavalent cholera toxin, scientist at the University of Leeds (UK), Wageningen University (Netherlands), and King Abdulaziz University in Jeddah (Saudi Arabia) have now developed a pentavalent inhibitor. To make it properly fit with its counterpart they fell back on the old principle of “fighting fire with fire”: They used an inactive version of the five “petals” from CTB subunits as the protein scaffold for their inhibitor.
Led by Bruce Turnbull, the researchers induced a mutation in the GM1 binding site of the CTB subunits so that the inhibitor does not bind to the intestinal cells. In addition, a special side chain on each of the “petals” was chemically altered so that they could undergo a coupling reaction by which five ligands were then attached with flexible spacers. The ligands were chosen to be the ideal binding partners for the toxin:
the saccharide units from glycolipid GM1. The advantage of this method is that the inhibitor presents the toxin with five ligands that are in exactly the same distance apart as the five binding sites of the toxin, making it the perfect counterpart. The potency of the new pentavalent inhibitor for its target molecule is thus correspondingly high.
Although the synthesis of the sugar motif is relatively complicated, the protein scaffold can easily be produced genetically on an industrial scale, and can easily be chemically modified and the saccharides attached. The researchers hope that this synthetic technique can be used to develop further multivalent inhibitors for other protein–carbohydrate interactions.
About the Author
Dr. Bruce Turnbull is an Associate Professor in the School of Chemistry and Astbury Centre for Structural Molecular Biology at the University of Leeds. He chairs an EU COST Action network on Multivalent Glycosystems for Nanoscience and was the 2013 recipient of the Royal Society of Chemistry Carbohydrate Award.
Author: W. Bruce Turnbull, University of Leeds (United Kingdom), http://www.chem.leeds.ac.uk/People/Turnbull.html
Title: A Protein-Based Pentavalent Inhibitor of the Cholera Toxin B-Subunit
Angewandte Chemie International Edition, Permalink to the article: http://dx.doi.org/10.1002/anie.201404397
W. Bruce Turnbull | GDCh
An evolutionary heads-up – The brain size advantage
22.05.2015 | Veterinärmedizinische Universität Wien
Endocrine disrupting chemicals in baby teethers
21.05.2015 | Goethe-Universität Frankfurt am Main
Physicists have developed an innovative method that could enable the efficient use of nanocomponents in electronic circuits. To achieve this, they have developed a layout in which a nanocomponent is connected to two electrical conductors, which uncouple the electrical signal in a highly efficient manner. The scientists at the Department of Physics and the Swiss Nanoscience Institute at the University of Basel have published their results in the scientific journal “Nature Communications” together with their colleagues from ETH Zurich.
Electronic components are becoming smaller and smaller. Components measuring just a few nanometers – the size of around ten atoms – are already being produced...
Development and implementation of an advanced automobile parking navigation platform for parking services
To fulfill the requirements of the industry, PolyU researchers developed the Advanced Automobile Parking Navigation Platform, which includes smart devices,...
The world's first electrical car and passenger ferry powered by batteries has entered service in Norway. The ferry only uses 150 kWh per route, which...
On Tuesday, 19 May 2015 the research icebreaker Polarstern will leave its home port in Bremerhaven, setting a course for the Arctic. Led by Dr Ilka Peeken from the Alfred Wegener Institute, Helmholtz Centre for Polar and Marine Research (AWI) a team of 53 researchers from 11 countries will investigate the effects of climate change in the Arctic, from the surface ice floes down to the seafloor.
RV Polarstern will enter the sea-ice zone north of Spitsbergen. Covering two shallow regions on their way to deeper waters, the scientists on board will focus...
Nanoengineers at the University of California, San Diego developed a gel filled with toxin-absorbing nanosponges that could lead to an effective treatment for skin and wound infections caused by MRSA (methicillin-resistant Staphylococcus aureus), an antibiotic-resistant bacteria. This "nanosponge-hydrogel" minimized the growth of skin lesions on mice infected with MRSA - without the use of antibiotics. The researchers recently published their findings online in Advanced Materials.
To make the nanosponge-hydrogel, the team mixed nanosponges, which are nanoparticles that absorb dangerous toxins produced by MRSA, E. coli and other...
20.05.2015 | Event News
18.05.2015 | Event News
12.05.2015 | Event News
22.05.2015 | Materials Sciences
22.05.2015 | Information Technology
22.05.2015 | Materials Sciences