title: Pharmaceutical strategies against amyloidosis: old and new drugs in targeting a "protein misfolding disease".
abstract: The group of diseases caused by abnormalities of the process of protein folding and unfolding is rapidly growing and includes diseases caused by loss of function as well as diseases caused by gain of function of misfolded proteins. Amyloidoses are caused by gain of function of certain proteins that lose their native structure and self-assemble into toxic insoluble, extracellular fibrils. This process requires the contribution of multiple factors of which only a few are established, namely the conformational modification of the amyloidogenic protein, protein's post-translational modifications and the co-deposition of glycosaminoglicans and of serum amyloid P component. In parallel with the exponential growth of biochemical data regarding the key events of the fibrillogenic process, several reports have shown that small molecules, through the interaction with either the amyloidogenic proteins or with the common constituents, can modify the kinetics of formation of amyloid fibrils or can facilitate amyloid reabsorption. These small molecules can be classified on the basis of their protein target and mechanism of action, according to the following properties. 1) molecules that stabilize the amyloidogenic protein precursor 2) molecules that prevent fibrillogenesis by acting on partially folded intermediates of the folding process as well as on low molecular weight oligomers populating the initial phase of fibril formation 3) molecules that interact with mature amyloid fibrils and weaken their structural stability 4) molecules that displace fundamental co-factors of the amyloid deposits like glycosaminoglycans and serum amyloid P component and favor the dissolution of the fibrillar aggregate.
authors.affiliation: Dipartimento di Chimica Farmaceutica, Università di Pavia, Italy.
authors.forename: Ersilia
authors.initials: E
authors.lastname: De Lorenzi
authors.forename: Sofia
authors.initials: S
authors.lastname: Giorgetti
authors.forename: Silvia
authors.initials: S
authors.lastname: Grossi
authors.forename: Giampaolo
authors.initials: G
authors.lastname: Merlini
authors.forename: Gabriele
authors.initials: G
authors.lastname: Caccialanza
authors.forename: Vittorio
authors.initials: V
authors.lastname: Bellotti
mesh_terms: D000682:Amyloid / Q000378:metabolism; D000686:Amyloidosis / Q000188:drug therapy* / Q000209:etiology*; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D007700:Kinetics; D008958:Models, Molecular; D008970:Molecular Weight; D017510:Protein Folding; D020836:Protein Structure, Quaternary / Q000187:drug effects; D011506:Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D000682:Amyloid; D000894:Anti-Inflammatory Agents, Non-Steroidal; D011506:Proteins