Peptide Stapling Improves the Sustainability of a Peptide-Based Chimeric Molecule That Induces Targeted Protein Degradation

International Journal of Molecular Sciences

Takao Inoue¹  Nobumichi Ohoka¹  Yosuke Demizu²  Keisuke Tsuchiya²  Hidetomo Yokoo²  Takahito Ito²  Mami Takyo²  Takashi Kurohara²  Kiyoshi Fukuhara³  Mikihiko Naito⁴ 

[1] Division of Molecular Target and Gene Therapy Products, National Institute of Health Sciences, 3-25-26, Kanagawa 210-9501, Japan;Division of Organic Chemistry, National Institute of Health Sciences, 3-25-26, Kanagawa 210-9501, Japan;Graduate School of Pharmacy, Showa University, Tokyo 142-0064, Japan;Laboratory of Targeted Protein Degradation, Graduate School of Pharmaceutical Sciences, The University of Tokyo, Tokyo 113-0033, Japan;

关键词: estrogen receptors;    helical peptide;    protein-protein interaction;    protein knockdown;   

DOI  :  10.3390/ijms22168772

来源: DOAJ

【 摘 要 】

Peptide-based target protein degradation inducers called PROTACs/SNIPERs have low cell penetrability and poor intracellular stability as drawbacks. These shortcomings can be overcome by easily modifying these peptides by conjugation with cell penetrating peptides and side-chain stapling. In this study, we succeeded in developing the stapled peptide stPERML-R7, which is based on the estrogen receptor alpha (ERα)-binding peptide PERML and composed of natural amino acids. stPERML-R7, which includes a hepta-arginine motif and a hydrocarbon stapling moiety, showed increased α-helicity and similar binding affinity toward ERα when compared with those of the parent peptide PERML. Furthermore, we used stPERML-R7 to develop a peptide-based degrader LCL-stPERML-R7 targeting ERα by conjugating stPERML-R7 with a small molecule LCL161 (LCL) that recruits the E3 ligase IAPs to induce proteasomal degradation via ubiquitylation. The chimeric peptide LCL-stPERML-R7 induced sustained degradation of ERα and potently inhibited ERα-mediated transcription more effectively than the unstapled chimera LCL-PERML-R7. These results suggest that a stapled structure is effective in maintaining the intracellular activity of peptide-based degraders.

【 授权许可】

Unknown