Emerging biologic modalities for targeted protein degradation

TL;DR

This paper reviews new biological methods to destroy harmful proteins in cells, offering a promising approach for treating diseases.

Contribution

The paper introduces and reviews novel biologic degraders for targeted protein degradation, expanding therapeutic possibilities.

Findings

Biologic degraders offer high specificity and can target proteins previously inaccessible to small molecules.

Peptide-based strategies bridge biologic and synthetic methods, enhancing TPD versatility.

Abstract

Targeted protein degradation (TPD) has emerged as a powerful approach for eliminating disease-associated proteins by harnessing the ubiquitin–proteasome system. Biologic degraders are modular protein chimeras that recruit ubiquitin machinery to target proteins. They offer high specificity, modular design, and the ability to access targets traditionally considered challenging for small-molecule ligands. This review surveys the expanding landscape of biologic TPD modalities, highlighting E3 ligase– and E2 enzyme–based degraders, TRIM-Away and TRIMbody-Away systems, and diverse biologics-based ligands that serve as target-binding components. We also discuss emerging peptide-based strategies, which bridge biologic and synthetic approaches. Finally, we highlight future opportunities to improve biologic degraders and their potential to expand the scope of TPD.

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