Highly promising drugs work less well in their natural environment
Researchers from the Biological Soft Matter group of the FOM Institute AMOLF and the Max Planck Institute in Mainz (Germany) have demonstrated that a highly promising drug against protein-related diseases works far less efficiently in the presence of a model membrane (as is also the case in-vivo) than had previously been thought on the basis of laboratory experiments without membranes. They published the results of this study on 27 August 2012 in the Journal of the American Chemical Society (JACS).
Diseases such as Alzheimer's and Creutzfeldt-Jacob are not caused by viruses, bacteria or fungi but by proteins that fold incorrectly in a specific structure. When, in essence harmless, biologically active proteins unfold, these have the tendency to assume a type of structure known as 'amyloid fibrils'. These fibrils can damage the cell membranes of brain cells, leading to damage and resulting in diseases. The amyloid fibrils formed from the protein hIAPP damage the membranes of insulin-producing cells and play a role in type II diabetes mellitus.
Inhibitory effect
Much research is focused on potential drugs that dissolve or prevent the formation of these amyloid fibrils. Polyphenols are a highly promising active substance in these inhibitory drugs. Researchers from the groups of Gijsje Koenderink and Mischa Bonn are the first to have investigated the effectiveness of the inhibitor EGCG against the formation of amyloids from the protein hIAPP in model membranes. EGCG, epigallocatechin gallate, is a polyphenol, which in previous in vitro experiments was found to both dissolve amyloids and prevent their formation. Up until now this had only been investigated in bulk solutions and not in the presence of membranes.
The researchers discovered that the inhibitory effect of EGCG in bulk solutions strongly decreased in the presence of a model membrane. The drug did not break down the amyloids formed and could only partially prevent the amyloids from forming on the membrane. It is assumed that amyloid fibrils form on the membrane of cells and cause specific damage there. The researchers have therefore concluded that drugs against amyloids must always be tested in the presence of model membranes and not just in solution.
Contact
Prof.dr. Gijsje Koenderink, +31 (0)20 754 71 90
Prof.dr. Mischa Bonn, +49 (0)613 137 91 60
Referentie
Maarten F.M. Engel, Corianne C. van den Akker, Michael Schleeger, Krassimir P. Velikov, Gijsje H. Koenderink and Mischa Bonn 'The polyphenol EGCG inhibits amyloid formation less efficiently at phospholipid interfaces than in bulk solution', J. Am. Chem. Soc. DOI: 10.1021/ja3031664.