Designing drugs to stop the formation of prion aggregates and other amyloids.
Amyloid protein aggregates are implicated in many neurodegenerative diseases, including Alzheimer's disease and the prion diseases. Therapeutics to block amyloid formation are often tested in vitro, but it is not clear how to extrapolate from these experiments to a clinical setting, where the effective drug dose may be much lower. Here we address this question using a theoretical kinetic model to calculate the growth rate of protein aggregates as a function of the dose of each of three categories of drug. We find that therapeutics which block the growing ends of amyloids are the most promising, as alternative strategies may be ineffective or even accelerate amyloid formation at low drug concentrations. Our mathematical model can be used to identify and optimise an end-blocking drug in vitro. Our model also suggests an alternative explanation for data previously thought to prove the existence of an entity known as protein X.
Masel
J
J
Wellcome Trust Centre for the Epidemiology of Infectious Disease, Department of Zoology, University of Oxford, UK. joanna.masel@zoo.ox.ac.uk
Jansen
V A
VA
D000682:Amyloid / Q000096:biosynthesis / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007700:Kinetics; D008956:Models, Chemical; D011108:Polymers / Q000378:metabolism; D011328:Prions / Q000187:drug effects / Q000378:metabolism*
D000682:Amyloid; D011108:Polymers; D011328:Prions