Leveraging peptides for targeted protein degradation.

BioPROTACs: a promising approach for targeted protein degradation.

TARGETED PROTEIN DEGRADATION WITH PROTACS IN CANCER THERAPY: MECHANISMS, CLINICAL ADVANCES, CHALLENGES, AND FUTURE PERSPECTIVES

This thorough analysis investigates the molecular basis of PROTAC technology, tracking its progression from an elegant intellectual notion to a clinically approved treatment platform and provides a detailed survey of the current clinical landscape.

Delivering Degradation: Nanomedicine and Programmable Proximity Platforms for Targeted Protein Degradation

Targeted protein degradation (TPD) represents a whole new paradigm in cell-level therapeutic design, with its ability to remove target proteins, normally through the endogenous proteasomal, lysosomal, or autophagic systems, rather than the traditional occupancy-driven inhibition approach. But the clinical efficacy of degraders is becoming more restricted based on delivery rather than efficacy only. Many proteolysis-targeting chimeras and new proximity-inducing systems have low solubility, are impermeable, are pharmacodynamically complicated, lack tissue selectivity, and cannot fully access the intracellular space. Nanomedicine and PD platforms could provide strategies not only to overcome these challenges, but also to provide other advantages, including enhancing exposure to degraders, biodistribution, controlled release, and context-dependent activation. This critical review is an outline of all lipid, polymeric, inorganic, biomimetic, targeted, activatable, and self-assembling delivery systems for TPD. We assess compositional considerations, in vitro and in vivo evidence, challenges for translation, and clinical endpoints required to support delivery-enabled degradation. Trusted TPD therapeutics need to relate different aspects of their design, such as degrader chemistry, carrier structure, disease biology, and pharmacodynamic biomarkers, to one another. Further investigations are needed to establish intact delivery of the degrader to the target, target depletion in relevant tissues, prolonged pharmacodynamics, favorable safety, and compelling therapeutic benefit relative to free degraders or traditional inhibitors. Thus, it is important to view delivery not simply as an additional step during formulation but as a design principle necessary for the reliable clinical outcome of degradation medicine.

PROTAC-Based Strategies in Neurodegenerative Diseases: Challenges and Perspectives

This review summarizes recent advances in chemical protein degradation strategies for neurodegenerative disorders and highlights potential future perspectives of multifunctional PROTACs for therapeutic development.

Macrocyclic peptides and peptidomimetics as modulators of protein-protein interactions.

Macrocyclic peptides and peptidomimetics (MPPs) have emerged as a powerful therapeutic class in peptide-based drug discovery, uniquely positioned to modulate challenging protein-protein interactions (PPIs). While dysregulated PPIs drive diverse human pathologies, including cancer, metabolic disorders, neurodegenerative proteinopathies, inflammatory conditions, and microbial infections, targeting them remains difficult. Traditional small molecules lack the surface area to bind large, flat PPI interfaces, whereas linear peptides suffer from rapid proteolytic degradation and poor cell permeability. MPPs overcome these limitations by bridging the gap between small molecules and biologics. Their cyclic architecture provides conformational rigidity minimizing entropic penalties and maximizing binding affinity and selectivity. This structural pre-organization also enhances metabolic robustness, protease resistance, and cellular permeability. This review comprehensively examines the biological significance of PPIs in human disease and details how MPPs effectively modulate historically undruggable targets. We highlight current synthetic strategies, peptide engineering platforms, and the clinical and preclinical status of leading MPP candidates, while weighing their operational advantages and limitations. Finally, we analyze the contemporary market trajectory and emerging commercial opportunities, positioning MPPs as next-generation, PPI-targeting therapeutics.

Artificial intelligence empowers targeted protein degradation: Core technological innovations, multi‐scenario applications, and translational prospects

This review systematically explores AI applications in TPD development, covering the prediction and design of stable ternary complexes, rational optimization of linkers, high‐throughput screening for E3 ligase ligands, and accurate predictions of degradation efficiency and ADMET properties.