Chemical modulation of protein-protein interactions can significantly impact therapeutic development for a variety of diseases. Peptides modeled on consensus recognition sequences driving critical protein-protein interactions potentially can serve as useful starting points for inhibitor development; however these tend to bind with low affinity.  While detailed tertiary structures of target proteins can guide ligand optimization, this information is often available late in the discovery process, and in some cases it is only of limited value. Taking advantage of the facile condensation of aminooxy functionality and carbonyl groups, we have incorporated aminooxy handles into consensus recognition sequences, and used these for post-solid phase construction of libraries of tethered components. These libraries can be easily constructed and directly evaluated to provide detailed SAR information for each amino acid residue, leading to enhancement of overall binding affinity. We will present our sucessful applications of this approach on the discovery of TSG101-directed HIV-1 budding antagonists, and the inhibitors of polo box domain (PBD) of polo-like kinase 1 (Plk1).

Peptide mimetics disrupting protein-protein interactions discovered by post-solid phase modifications

240th National Meeting (2010)

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