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Automated Robotic Liquid Handling Assembly of Modular DNA Devices

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Molecular glue degraders: Rational design, specificity engineering, and advanced delivery.

Lieen Ma¹, Ning Wang², Jingjing Zhu³

¹School of Pharmacy, Health Science Center, Ningbo University, Ningbo 315211, China.

Acta Pharmaceutica Sinica. B

|July 15, 2026

Summary

Molecular glue degraders (MGDs) offer a novel approach to targeted protein degradation (TPD). This review outlines a framework for rational MGD design, specificity optimization, and delivery systems to advance their therapeutic potential.

Keywords:

Drug delivering systems E3 ligases Molecular glue degraders Rational design Specificity engineering Targeted protein degradation

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Area of Science:

Drug Discovery and Development
Molecular Biology
Biochemistry

Background:

Molecular glue degraders (MGDs) represent a significant advancement in targeted protein degradation (TPD).
MGDs utilize monovalent architectures to induce protein-protein interactions (PPIs) between E3 ligases and neosubstrates, differing from bifunctional PROTACs.
Current MGD discovery is largely serendipitous, lacking a robust framework for rational design, selectivity, and tissue exposure.

Purpose of the Study:

To present an integrated framework for developing next-generation MGDs.
To explore strategies for rational design, specificity optimization, and delivery systems for MGDs.
To highlight emerging opportunities for accelerating MGD discovery and clinical translation.

Main Methods:

Review of cutting-edge MGD design strategies, including covalent reprogramming and PPI stabilization.
Exploration of structure-guided engineering and chemoinformatic models for neosubstrate selectivity.
Summary of delivery platforms such as antibody-drug conjugates and nanoparticle systems for targeted distribution.

Main Results:

Identification of advanced MGD design approaches.
Methods for enhancing neosubstrate selectivity and minimizing off-target effects.
Overview of delivery systems to improve tissue selectivity and accumulation.

Conclusions:

The integrated framework provides a roadmap for advancing MGDs.
Interdisciplinary insights underscore the therapeutic promise of MGDs in precision medicine.
Further development in AI, structural biology, and systems pharmacology will accelerate MGD discovery and translation.