Synthesis and Evaluation of Macrocyclic Peptide Aldehydes as Potent and Selective Inhibitors of the 20S Proteasome
详细信息 查看全文
- 作者：David L. Wilson ; Isabel Meininger ; Zack Strater ; Stephanie Steiner ; Frederick Tomlin ; Julia Wu ; Haya Jamali ; Daniel Krappmann ; Marion G. Götz
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2016
- 出版时间：March 10, 2016
- 年：2016
- 卷：7
- 期：3
- 页码：250-255
- 全文大小：384K
- ISSN：1948-5875
文摘
This research explores the first design and synthesis of macrocyclic peptide aldehydes as potent inhibitors of the 20S proteasome. Two novel macrocyclic peptide aldehydes based on the ring-size of the macrocyclic natural product TMC-95 were prepared and evaluated as inhibitors of the 20S proteasome. Both compounds inhibited in the low nanomolar range and proved to be selective for the proteasome over other serine and cysteine proteases, particularly when compared to linear analogues with similar amino acid sequences. In HeLa cells, both macrocycles efficiently inhibited activation of nuclear factor-κB (NF-κB) transcription factor by blocking proteasomal degradation of the inhibitor protein IκBα after cytokine stimulation. Due to their covalent mechanism of binding these compounds represent a 1000-fold increase in inhibitory potency over previously reported noncovalently binding TMC-95 analogues. Molecular modeling of the macrocyclic peptides confirms the preference of the large S3 pocket for large, hydrophobic residues and the ability to exploit this to improve selectivity of proteasome inhibitors.