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Updated: Mar 27, 2026

Sequence-specific Labeling of Nucleic Acids and Proteins with Methyltransferases and Cofactor Analogues
Published on: November 22, 2014
Affinity enhancement of polo-like kinase 1 polo-box domain-binding peptides by N-methylation and lipidation
Kohei Tsuji1, Kenan Bai1, Xueyuan Huang1
1Department of Medicinal Chemistry, Laboratory for Biomaterials and Bioengineering, Institute of Integrated Research, Institute of Science Tokyo, 2-3-10 Kandasurugadai, Chiyoda-ku, Tokyo 101-0062, Japan. ktsuji.mr@tmd.ac.jp.
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.
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