Abstract:

The folding and supramolecular assembly of peptides are central to their biological function. In Alzheimer’s disease, amyloid beta (Aβ) assembles into soluble neurotoxic oligomers. The structures formed by these soluble oligomers remain poorly understood due to their heterogeneity and metastability. To better understand the structures formed by soluble Aβ oligomers, I characterized a model peptide that mimics that Aβ16-36 hairpin. I discovered this model peptide assembles into a symmetric hexamer in the crystallographic state but assembles into an asymmetric hexamer in aqueous solution. Subsequent DOSY and MD simulations reveal how two asymmetric hexamers can further assemble into a dodecamer. The second half of the talk describes the first synthesis of hypeptin, a gram-positive cyclodepsipeptide antibiotic that contains unusual patterns of β-hydroxylation. I detail the syntheses of the hydroxytyrosine and hydroxyleucine amino acid building blocks used in the failed first-generation synthesis of hypeptin. Based on learnings from the failed synthesis, I describe the successful second-generation synthesis of hypeptin. It is hoped that these studies will enable the further development of the hypeptin scaffold as a potential antibiotic candidate.