Design and synthesis of fluorinated peptides for analysis of fluorous effects on the interconversion of polyproline helices.

The unique interaction between fluorine atoms has been exploited to alter protein structures and to develop synthetic and analytical applications. To expand such fluorous interaction for novel applications, polyproline peptides represent an excellent molecular nanoscaffold for controlling the presentation of perfluoroalkyl groups on their unique secondary structure. We develop approaches to synthesis fluorinated peptides to systematically investigate how the number, location and types of the fluorous groups on polyproline affect the conformation by monitoring the transition between the two major polyproline structures PPI and PPII. This work provides valuable information on how fluorous interaction affects the peptide structure and also benefits the design of functional fluorous molecules.

Controlling Ligand Spacing on Surface: Polyproline-Based Fluorous Microarray as a Tool in Spatial Specificity Analysis and Inhibitor Development for Carbohydrate-Protein Interactions.

Multivalent carbohydrate-protein interactions are essential for many biological processes. Convenient characterization for multivalent binding property of proteins will aid the development of molecules to manipulate these processes. We exploited the polyproline helix II (PPII) structure as molecular scaffolds to adjust the distances between glycan ligand attachment sites at 9, 18, and 27 Å on a peptide scaffold. Optimized fluorous groups were also introduced to the peptide scaffold for immobilization to the microarray surface through fluorous interaction to control the orientation of the helical scaffolds. Using lectin LecA and antibody 2G12 as model proteins, the binding preference to the 27 Å glycopeptide scaffold, matched the distance of 26 Å between its two galactose binding sites on LecA and 31 Å spacing between oligomannose binding sites on 2G12, respectively. We further demonstrate this microarray system can aid the development of inhibitors by transforming the selected surface-bound scaffold into multivalent ligands in solution. This strategy can be extended to analyze proteins that lacking structural information to speed up the design of potent and selective multivalent ligands.