Abstract: Peptides and small molecules are often at odds when it comes to their ease of synthesis, solubility, biological applications, and other uses. However, in this thesis defense I will aim to explore the synergy between small molecules and peptides, and how small molecules can be used in studying and creating biologically relevant peptides.
The first part of the talk focuses on the design, synthesis, and study of a photoaffinity probe for Aβ oligomers – crystal violet diazirine (CrVD). This chemical probe can tag and identify Aβ oligomers, which are involved in neurodegeneration in Alzheimer's disease. Crystal violet is a useful tool for identifying toxic peptide models but lacks the ability to capture oligomeric species through covalent bond formation. To address this, CrVD was designed as an isosteric analogue with a photoaffinity labeling probe, and synthesized from α,α,α-trifluoroacetophenone. Mass spectrometric analysis established that crystal violet diazirine selectively labels a synthetic trimer previously developed in our laboratory. CrVD also labels full-length Aβ and it differentiates between monomeric or oligomeric Aβ and fibrillar Aβ.
The second part of the talk focuses on Novo29, a new peptide antibiotic related to teixobactin, active against Gram-positive bacteria without inducing antibiotic resistance. Novo29 is an eight-residue depsipeptide containing the noncanonical amino acid hydroxyasparagine with hitherto undetermined stereochemistry. Using (R,R)- and (S,S)-diethyl tartrate Fmoc-(2R,3R)-hydroxyasparagine-OH and Fmoc-(2R,3S)-hydroxyasparagine-OH were synthesized and then used as building blocks in solid-phase peptide synthesis for Novo29 and epi-Novo29 respectively. Novo29 contains (2R,3R)-hydroxyasparagine, as established by NMR spectroscopy, LC-MS, and in vitro antibiotic activity. Crystallography, and molecular modeling suggests that Novo29 may interact with bacteria in a similar way to teixobactin.