Designed peptide binders and nanobodies as PROTAC starting points for targeted degradation of PCNA and BCL6.

in International journal of biological macromolecules by Shuai Zhao, Jingwen Luo, Pingping Xu, Jingwei Zeng, Guangbo Yan, Fang Yu, Liwei Qin, Cheng Zhang, Peng Li, Mengxing Cai, Wuxiang Mao, Chin-Yu Chen, Wanping Chen, Rui Han, Fei Wang, Yang Wang, Lixin Ma

TLDR

  • The study develops a bioPROTACs system that efficiently degrades pathogenic proteins PCNA and BCL6, thereby activating p53 and promoting apoptosis, and highlights the therapeutic potential of targeting these proteins.
  • The system offers a modular and rapid pathway for exploring other intractable therapeutic targets and emphasizes the importance of interdisciplinary methods in advancing therapeutic interventions.
  • The results have significant implications for developing novel treatments for various diseases, including cancer.

Abstract

The efficient degradation of pathogenic proteins, particularly proliferating cell nuclear antigen (PCNA) and B-cell lymphoma 6 protein (BCL6), is crucial for treating various diseases related to cancer. As key biological macromolecules, PCNA plays a critical role in DNA replication and repair, while BCL6 acts as a transcriptional repressor involved in B-cell lymphoma. To enhance the efficiency and specificity of protein degradation, we developed a RS80E-based bioPROTACs system that consists of truncated variants of Ring-B-boxed coiled-coil (RBCC) domains (RS80E) with improved degradation efficiency fused to an AI-driven binder/nanobody targeting specific antigens. Combining state-of-the-art methodologies such as ProteinMPNN, RFdiffusion, AlphaFold3, AlphaFold2, and HADDOCK, we identified binders for PCNA and predicted spatial interrelationships. Employing fragment-based and alanine scanning methods, we designed nanobodies targeting PCNA and BCL6 by combinatorially designing CDR3 and grafting them onto nanobody scaffolds. Significantly, our results demonstrate the utility of bioPROTACs in degrading PCNA and BCL6, thereby activating p53 and promoting apoptosis. This highlights the therapeutic potential of targeting PCNA and BCL6 degradation and lays the groundwork for developing PCNA and BCL6-degrading therapeutics. In summary, our system offers a modular and rapid pathway for exploration other intractable therapeutic targets, and emphasizes the importance of interdisciplinary methods in advancing therapeutic interventions.

Overview

  • The study focuses on developing a system for efficient degradation of pathogenic proteins PCNA and BCL6, which are crucial for treating various diseases related to cancer.
  • The system, called bioPROTACs, consists of truncated RBCC domains (RS80E) fused to AI-driven binders/ nanobodies targeting specific antigens.
  • The primary objective of the study is to develop a bioPROTACs system that can efficiently degrade PCNA and BCL6, thereby activating p53 and promoting apoptosis.

Comparative Analysis & Findings

  • The study used a combination of state-of-the-art methodologies, including ProteinMPNN, RFdiffusion, AlphaFold3, AlphaFold2, and HADDOCK, to identify binders for PCNA and predict spatial interrelationships.
  • The results demonstrate the utility of bioPROTACs in degrading PCNA and BCL6, thereby activating p53 and promoting apoptosis.
  • The degradation of PCNA and BCL6 highlights the therapeutic potential of targeting these proteins and lays the groundwork for developing PCNA and BCL6-degrading therapeutics.

Implications and Future Directions

  • The study emphasizes the importance of interdisciplinary methods in advancing therapeutic interventions and offers a modular and rapid pathway for exploring other intractable therapeutic targets.
  • Future research directions could focus on applying the bioPROTACs system to other diseases and exploring novel approaches for targeting specific proteins.
  • The development of bioPROTACs therapeutics could lead to novel treatments for various diseases, including cancer, and improve patient outcomes.
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