Peptide-Based Molecular Glues for Targeted Protein Degradation

Abstract

Targeted protein degradation has transformed drug discovery by replacing occupancy-driven inhibition with event-driven removal of disease-causing proteins, opening previously “undruggable” targets, including transcription factors, scaffolding proteins, and intrinsically disordered regions, to therapeutic intervention. Within this landscape, peptide-based molecular glues have emerged as a distinct and underexplored modality, combining the extended, adaptable interaction surfaces of peptides with the mechanistic simplicity of induced-proximity pharmacology. Unlike bifunctional degraders such as PROTACs, which require the concurrent optimization of two linked ligands, peptide molecular glues act through a single engineered interface, stabilizing cooperative ternary complexes between a target protein and an E3 ubiquitin ligase to drive ubiquitination and proteasomal degradation. This review highlights the current understanding of peptide molecular glue biology across five interconnected dimensions: the mechanistic basis of E3 ligase recruitment and cooperative ternary complex formation; rational design strategies spanning sequence selection, structural stabilization, and computational and AI-guided optimization; the structural and biophysical determinants, such as conformational flexibility, interface complementarity, and thermodynamic and kinetic stability, that distinguish productive from non-productive complexes; and emerging therapeutic applications in oncology, hematological malignancy, neurodegeneration, and inflammatory disease, several of which have already reached clinical evaluation. We further examine the comparative advantages of peptide-based architectures, including reduced molecular weight, access to challenging interfaces, and expansion of the addressable E3 ligase repertoire, against persistent translational barriers in proteolytic stability, membrane permeability, immunogenicity, and manufacturability. Taken together, the evidence positions peptide-based molecular glues not as incremental variants of existing degrader platforms, but as a mechanistically distinct therapeutic class capable of substantially widening the druggable proteome.