Nanobody-Based Targeted Protein Degradation

Dear colleagues,

Targeted protein degradation (TPD) has emerged as a new modality in drug discovery. It can be classified into three categories based on the specific mechanism of degradation: (i) ubiquitin–proteasome system (UPS)-based TPD, (ii) autophagy-based TPD, and (iii) endosomal–lysosomal-system- or endocytic pathway-based TPD, all of which rely on various proteases to cleave or degrade unwanted proteins. UPS-based approaches primarily degrade soluble intracellular proteins, autophagy-based TPD covers a wider range of substrates including protein aggregates and organelles, while endocytic pathway-based TPD enables the targeted degradation of extracellular and membrane proteins. Among the various degraders, bifunctional small-molecule degraders carry a warhead that recruits a protein of interest (target protein) and another module that directs it to the respective degradation pathway. These bifunctional small-molecule degraders are cell-permeable and easy to use. However, their preparation through multi-step organic synthesis can be challenging, and they may exhibit unpredictable pharmacological activities, occasionally leading to the so-called hook effect. Additionally, addressing unligandable targets with these degraders can be difficult.

Nanobodies, a single-chain variable domain of heavy-chain-only antibodies (V_HH) derived from camels, are known for their compact size (~15 kDa, about one-tenth of the size of a traditional antibody), high stability, strong binding affinity, high specificity, and ease of generation through bacterial expression. The advantages of nanobodies over small-molecule binders are their generality and modularity, as they can be generated using the same pipeline, such as camelid immunization and subsequent nanobody screening. Additionally, nanobodies have the ability to target undruggable or unligandable proteins; they also hold great potential for binding specific mutant forms of disease-causing proteins. Therefore, integrating nanobody technology with TPD holds great promise. Traditionally, nanobody chimera degraders have been expressed inside living cells in the form of intrabodies. With the advancements in more effective intracellular delivery systems, such as the cyclic-arginine-rich peptide-based delivery system, it is now possible to deliver nanobody chimeras or nanobody conjugates into cells in a non-endocytic fashion to degrade intracellular proteins.

In this Special Issue, we are soliciting research papers on the topic of nanobody-based targeted protein degradation. The focus will be on papers addressing nanobody-based TPD through the UPS, endocytic, and autophagic pathways, as well as alternative mechanisms, and new platforms for the delivery of nanobody-based degraders into living cells.

Dr. Xi Chen
Guest Editor

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• nanobody
• targeted protein degradation (TPD)
• UPS system
• autophagy
• endosomal–lysosomal pathway
• hook effect
• small-molecule–nanobody conjugate-induced proximity (SNACIP)