Affinity enhancement of polo-like kinase 1 polo-box domain-binding peptides by N-methylation and lipidation

Abstract

Cell membrane permeability is one of the biggest issues for bioactive peptides targeting intracellular proteins because of their high polarity and flexibility. To overcome this issue, cell-penetrating peptides (CPPs) are often attached to peptides. Additional approaches include backbone modifications, such as N-methylation and lipidation, which increase structural rigidity and hydrophobicity. Herein, we synthesized and evaluated N-methylated or lipidated Plk1 PBD-binding peptides. N-Methylated and lipidated analogs showed up to 4-fold and 260-fold enhanced PBD affinities, respectively, as compared with the parent PBD-binding peptide. However, none of these analogs showed significant cytotoxicity against HeLa cells. These results suggest that further optimization is required to develop practical Plk1 PBD-binding inhibitors that exhibit cellular activities.