Adaptor-specific peptide inhibitors of the ubiquitin-chain-dependent unfolding activity of the human p97(VCP)–UFD1–NPL4 complex 

Kei Okatsu1, Takaya Kawaguchi, Kohei Watanabe, Yoshinori Taguchi, Reon Takeuchi, Akinori Okamoto, Yasuyuki Iwasa, Takuya Tomita, Yasushi Saeki, Yusuke Sato,* Tetsuo Narumi,* & Shuya Fukai*

J. Med. Chem., 2025, 68, 11270.

The AAA-ATPase p97, a key component of the ubiquitin-proteasome system (UPS), collaborates with its cofactor, the UFD1–NPL4 (UN) heterodimer, to unfold ubiquitinated substrates leading to proteasomal degradation. In this study, we report the development of novel peptide inhibitors that specifically target the p97–UN complex. These inhibitors are designed based on the NPL4-binding motif (NBM) of UFD1 and disrupt the interaction between p97 and the UN heterodimer. Our results demonstrate that these peptides effectively inhibit the unfolding activity of p97–UN, suggesting their potential as a therapeutic strategy for diseases associated with UPS dysfunction, such as cancer and neurodegenerative disorders. This work provides the first mechanistic insights into the inhibition of p97–UN by high-affinity peptide inhibitors and introduces promising candidates for drug development targeting the stable p97–UN complex in cells.