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We are trying to design inhibitors
of therapeutically relevant protein-protein interactions in
which a beta-peptide mimics one of the two protein partners
(see figure). Beta-peptides have been shown to adopt well-defined
helical conformations in aqueous solution, making them good
scaffolds for displaying a broad range of functional groups
with particular spatial orientations. These structural properties
make beta-peptides good candidates for mediators of protein-protein
interactions, where the precise placement of sidechains in
the interface is mandatory for strong interaction.
Our effort to develop beta-peptide
inhibitors of protein-protein interactions involves three
primary disciplines or techniques: molecular modeling, organic
synthesis, and peptide synthesis. The potential inhibitors
are designed using molecular modeling and docking calculations
(if a structure of the protein target is available). Suitably
protected beta-amino acid monomers must then be synthesized
in enantiomerically-pure form for incorporation into the designed
peptides. Finally, solid-phase peptide synthesis (SPPS) is
used to make libraries of beta-peptides for assay.
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