Macromolecular design for modulation of amyloid fibrillar assembly

["Alzheimers disease";self-assembly;protein aggregation;modulation;bioconjugation;amyloid;polymer;peptide

Song, Yang

关键词: ["Alzheimers disease";    self-assembly;    protein aggregation;    modulation;    bioconjugation;    amyloid;    polymer;    peptide;   

Others  :  https://www.ideals.illinois.edu/bitstream/handle/2142/95481/SONG-DISSERTATION-2016.pdf?sequence=1&isAllowed=y

美国|英语

来源: The Illinois Digital Environment for Access to Learning and Scholarship

【 摘 要 】

Amyloid protein aggregation is notorious for its association with many devastating human diseases such as AIDS, cancer, Alzheimer's disease, and prion diseases. Scientists have made significant progress in designing modulators which prevent amyloid formation and provide potential therapeutics for amyloid-related diseases. Recently, extensive studies indicate that the elusive oligomeric intermediates, rather than the most visible amyloid fibrils, are the cause of cytotoxicity in amyloid aggregation. However, the rational design of synthetic modulators that specifically target the toxic oligomer intermediates and regulate the final shape and size of amyloid assemblies remains a challenge. Breakthroughs in this area provide insight and understanding for the toxic oligomer intermediates and the mechanism of amyloid protein aggregation. The fundamental studies on molecular level also provide the potential foundation for promising solutions to investigate amyloid-related diseases. This dissertation describes a new class of rationally designed polymeric modulators which specifically target amyloid β oligomers and control amyloid aggregation. Chapter 2-3 focus on the design of series of polymer-peptide conjugates which redirect Aβ fibrillar assembly by stabilizing Aβ oligomers into structurally well-defined discrete nanostructures. The modulatory effect was achieved by taking advantages of nucleation-dependent mechanism of Aβ aggregation. We investigated the influence of multivalency and specificity of molecular structures and optimized the Aβ modulatory effect by tuning molecular weights of polymers, as well as the loading ratio and the sequences of the attached Aβ recognition peptides. Chapter 4 describes the extended application of polymer-peptide conjugates as fibril breakers to dissociate preformed Aβ fibrils, and the dissociation rate is dependent on the molecular weight of conjugates. Chapter 5 reports the design of polyethylenimine-perphenazine conjugates as dual modulators which accelerate the formation of Aβ prefibrillar intermediates and inhibit the following fibrillation. The above polymeric conjugates are proved to detoxify Aβ oligomers and the results of MTT cell viability assays are summarized in Chapter 6. Our molecular design may thus represent a prototype of multivalent macromolecules that control the amyloid fibrillar assembly via a nucleation-dependent mechanism. It remains to be seen if this design concept is broadly applicable to the control of other molecular self-assembly process.