Supramolecular Assembly of Peptides Derived from Amyloid-beta (Abeta) and Development of Peptide Antibiotic

Soluble oligomers of amyloid-beta (Abeta) have been implicated as the culprit for neurodegeneration in Alzheimer's disease. Familial mutations of Abeta can lead to early-onset Alzheimer's disease. Structures of fibrils formed by wild-type Abeta and Abeta familial mutants differ. Structural elucidation of Abeta oligomers containing Abeta familial mutations may further our understanding of the disease. High resolution structures of Abeta oligomers can provide useful information for medicinal chemists to design therapeutics to treat Alzheimer's disease. The first chapter of this dissertation describes the X-ray crystallographic structures of two macrocyclic beta-sheets containing Abeta familial mutations. The oligomeric structures of these two macrocyclic beta-sheets are slightly different than the structure from the macrocyclic beta-sheet containing the wild-type Abeta sequence. Preliminary results of cytotoxicity studies showed that some Abeta familial mutants are more toxic toward neuronal cells than the wild-type Abeta. The findings of this chapter are significant, because the newly elucidated chemical models of Abeta oligomers containing Abeta familial mutations can potentially provide insights to early-onset Alzheimer's disease. Supramolecular assemblies of Abeta are interesting to investigate, because they are central in Alzheimer's disease.;They also act as a good starting point to study molecular recognition of peptides and fabrication of nanostructures. The second chapter of this dissertation describes the X-ray crystallographic structure of an Abeta-inspired macrocyclic beta-sheet that forms a giant double-walled nanotube. Monomers of the macrocyclic beta-sheet adopt two different conformations. The size of the nanotube rivals the size and complexity of the largest tubular biomolecular assemblies, such as microtubules. The findings of this chapter are significant, because a peptide nanotube of this size cannot currently be predicted from the Abeta16--22 sequence.;Structural chemists are interested in understanding the rules that govern molecular recognition and self-assembly of peptides. Currently, it is difficult to predict self-assembly of peptides, and the resulting oligomeric structures. The third chapter of this dissertation describes a different X-ray crystallographic structure formed from an analogue of the macrocyclic beta-sheet that yielded the peptide nanotube. The new macrocyclic beta-sheet has the same peptide sequence with a different beta-turn stabilizer. Changing the beta-turn stabilizer eliminates some existing molecular interactions. As a result, the new structure is very different than the peptide nanotube. The structural difference is yet another example that self-assembly of peptides cannot be reliably predicted. The findings of this chapter are significant, because they demonstrate that simple peptide modifications can induce an alternative supramolecular assembly from the same Abeta peptide sequence.;Teixobactin is a promising recently discovered antibiotic. The undecapeptide contains a 13-membered macrolactone ring and a non-proteinogenic amino acid allo-enduracididine. Teixobactin can kill drug-resistant Gram-positive bacteria without acquiring antibiotic resistance. Teixobactin binds to bacterial cell wall precursors such as lipid II and inhibits bacterial cell wall biosynthesis, which leads to cell lysis. The fourth and last part of this dissertation describes an alanine scan of Lys10-teixobactin. This traditional structure-activity-relationship study revealed that the cationic allo-enduracididine is not necessary for activity. The solubility, cytotoxicity, and hemolytic activities of these alanine scan analogues were evaluated. Reduced aqueous solubility correlates with better antibiotic activity. The alanine scan analogues are non-cytotoxic and non-hemolytic. The findings of this chapter are significant, because the results from the alanine scan of a teixobactin analogue provides a solid foundation to guide future teixobactin analogue design.