title: Chemical kinetics for drug discovery to combat protein aggregation diseases.
abstract: Protein misfolding diseases are becoming increasingly prevalent, yet there are very few effective pharmacological treatments. The onset and progression of these diseases is associated with the aberrant aggregation of normally soluble proteins and peptides into amyloid fibrils. Because genetic and physiological findings suggest that protein aggregation is a key event in pathogenesis, an attractive therapeutic strategy against this class of disorders is the search for compounds able to interfere with this process, in particular by suppressing the formation of soluble toxic oligomeric aggregates. In this review, we discuss how chemical kinetics can contribute to the fundamental understanding of the molecular mechanism of aggregation, and speculate on the implications for the development of therapeutic molecules that inhibit specific steps in the aggregation pathway that are crucial for preventing toxicity.
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Paolo
authors.initials: P
authors.lastname: Arosio
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Michele
authors.initials: M
authors.lastname: Vendruscolo
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Dobson
authors.affiliation: Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge CB2 1EW, UK. Electronic address: tpjk2@cam.ac.uk.
authors.forename: Tuomas P J
authors.initials: TP
authors.lastname: Knowles
mesh_terms: D055808:Drug Discovery; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D019636:Neurodegenerative Diseases / Q000188:drug therapy / Q000378:metabolism; D017510:Protein Folding / Q000187:drug effects; D011506:Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D057165:Proteostasis Deficiencies / Q000188:drug therapy* / Q000378:metabolism*
chemical_list: D011506:Proteins
keywords: aggregation kinetics; inhibition mechanism; neurodegenerative diseases; therapeutics