beta-Sheet Macrocycles that Mimic Amyloid Oligomers and Inhibit Amyloid Aggregation

The chemical models of protein beta-sheets described herein provide tools to address amyloid aggregation through beta-sheet interactions. Amyloid aggregation and oligomers are now recognized as central in many devastating human diseases such as AIDS, cancer, Alzheimer's disease, prion diseases, and amyloid-related diseases. This dissertation describes new insights gained through chemical models into the rich supramolecular chemistry of beta-sheets, particularly in amyloid aggregation and oligomers.;Chapter 1 provides representative examples of beta-sheet structures and interactions that occur ubiquitously in proteins and amyloids. It particularly points out the importance of the beta-sheet structures and interactions in amyloid aggregation associated with human diseases. Chapter 1 also describes insights into the edge-to-edge hydrogen-bonding interactions and face-to-face hydrophobic interactions among beta-sheets. By understanding and using the common features of protein beta-sheets, it may be possible to gain unique insights with which to further control beta-sheet interactions in Alzheimer's and other diseases.;Chapter 2 describes the development of amyloid beta-sheet mimics (ABSMs), a family of robust beta-sheet macrocycles that can display a variety of amyloidogenic sequences from different amyloid proteins. ABSMs contain a 54-membered ring comprising a heptapeptide beta-strand (the upper strand), one tripeptide beta-strand mimic Hao flanked by two dipeptides (the lower strand), and two beta-linked ornithine turns. This chapter also describes the structures and inhibitory properties of ABSMs that can be tailored to antagonize aggregation of various amyloid proteins such as amyloid beta-peptide associated with Alzheimer's disease, thereby reducing toxicity of amyloid aggregates. The crystallographic structures of ABSMs suggest structural models that provide insights into the elusive structures of amyloid fibrils and oligomers.;Chapter 3 reports the development of a series of heterodivalent linked macrocyclic beta-sheets that are not only far more active against Abeta aggregation than their monovalent components, but also are dramatically more active than their homodivalent counterparts. This chapter also includes a model to explain the enhanced activity of the heterodivalent compounds against Abeta aggregation. The work described in this chapter suggests a design strategy for inhibitors of amyloid aggregation, that is, polyvalent inhibitors that can target multiple regions of amyloidogenic peptides and proteins are better than those that only target a single region.;Chapter 4 describes a side project derived from chapters 2 and 3. It demonstrates an attempt to use natural amino acids, the tripeptide beta-strand mimic Hao, and the beta-turn mimic beta-linked ornithine to generate water-soluble 54-, 78-, and 102-membered ring macrolactams. It also demonstrates the powerful macrocyclization that helps these giant macrocylces fold into beta-sheet structures and reports a synthesis route with which these macrocycles were efficiently synthesized.