What is the difference between Lytac and PROTAC?
Targeted Protein Degradation represents an emerging molecular intervention strategy developed to overcome the long-standing “drugability” bottleneck of traditional inhibition-based therapies. Unlike small-molecule inhibitors that rely on the presence of an active binding pocket, targeted protein degradation uses two major intracellular clearance systems, the ubiquitin proteasome system and the endocytosis lysosome pathway, to tag and eliminate unwanted proteins. As an event-driven mechanism, it does not depend on sustained target occupancy, offering longer pharmacological effects and expanded target accessibility. This approach has opened new possibilities for modulating previously “undruggable” targets such as transcription factors, scaffolding proteins, and membrane-associated proteins, making targeted protein degradation one of the fastest-growing areas in drug discovery.
As research in this field accelerates, the demand for integrated analytical platforms capable of supporting degrader design and mechanistic validation continues to grow. To address these needs, MtoZ Biolabs has established a comprehensive platform dedicated to tools such as PROTAC and LYTAC. This platform integrates proteomics, interactomics, and ubiquitination analysis to provide end-to-end research services, covering target identification, profiling of E3 ligases or lysosomal receptors, quantitative degradation assessment, and mechanism validation. It incorporates experimental layers including cell model development, quantitative mass spectrometry, and immunofluorescent colocalization to support systematic and data-driven investigations in targeted protein degradation.
Mechanistic Overview: Molecular Design Strategies of Two Degradation Pathways
1. PROTAC: Enabling Intracellular Protein Degradation via the Proteasome
PROTACs are bifunctional small molecules inspired by the endogenous ubiquitin–proteasome system. Each PROTAC molecule consists of three modules:
-
Warhead, a small-molecule ligand with high affinity for the protein of interest (POI);
-
E3 ligase ligand, a ligand that recruits an intracellular E3 ubiquitin ligase, commonly CRBN (Cereblon) or VHL (Von Hippel–Lindau);
-
Linker, a flexible or rigid spacer that facilitates stable ternary complex formation between the warhead and E3 ligand.
Mechanistically, PROTACs bridge the target protein and E3 ligase, leading to covalent ubiquitination of the target. The ubiquitinated protein is then recognized and degraded by the 26S proteasome into short peptides, effectively removing it from the cell. Because PROTACs function through an event-driven process, each molecule can catalytically induce degradation of multiple copies of the target protein. This mechanism allows high efficiency, sustained pharmacological activity, and potentially lower effective doses compared to classical inhibitors.
2. LYTAC: Extending Protein Degradation to Membrane and Extracellular Targets
The advent of LYTAC technology overcomes the limitation of PROTACs, which act exclusively on intracellular proteins. LYTACs exploit the lysosomal degradation pathway and typically consist of an antibody or antibody–ligand conjugate comprising two key components:
-
Target-recognition moiety, such as a full-length antibody, Fab fragment, or engineered binding protein that specifically recognizes membrane or secreted proteins;
-
Lysosome-targeting ligand (LTL), often a mannose-6-phosphate (M6P) glycan that binds the CI-M6PR receptor on the cell surface, facilitating internalization.
Upon binding the target protein, the LYTAC complex engages the CI-M6PR receptor, is internalized through endocytosis, and traffics along the endosome–lysosome axis where the target protein is degraded. Unlike PROTACs, LYTACs act independently of the ubiquitin system, enabling selective removal of non-ubiquitinated or membrane proteins and thereby expanding the spectrum of degradable targets.
Distinct Target Scopes and Functional Implications
A defining advantage of targeted protein degradation technologies is their ability to transcend conventional target boundaries. PROTACs and LYTACs complement each other in their range of accessible proteins, providing synergistic potential in therapeutic development, target validation, and mechanistic research.
1. PROTACs for “Undruggable” Intracellular Proteins
Traditional small molecules act on only a fraction of the proteome with accessible binding pockets, leaving many essential regulators such as transcription factors unaddressable. PROTACs bypass this limitation by recruiting intracellular proteins into the ubiquitin system through high-affinity ligands, independent of enzymatic activity. Representative examples include ARV-110, which targets the androgen receptor in prostate cancer, and ARV-471, which degrades the estrogen receptor for breast cancer therapy.
2. LYTACs for Membrane and Secreted Protein Degradation
LYTACs extend targeted protein degradation to the extracellular environment, making it possible to eliminate membrane and secreted proteins critical for signaling, immune regulation, and tumor microenvironment control. For example, PD-L1, a major immune checkpoint protein, can be degraded using LYTACs, providing an alternative to traditional antibody blocking. Similarly, EGFR, a receptor tyrosine kinase overexpressed in various cancers, can be downregulated via lysosomal targeting. The use of tissue-specific receptors such as ASGPR also allows organ-targeted degradation, enabling liver-specific applications.
Structural and Engineering Challenges
The design of PROTACs involves optimizing ternary complex geometry, linker length, and cellular permeability. Their relatively large molecular weight often introduces challenges related to pharmacokinetics, plasma stability, and bioavailability.
For LYTACs, difficulties include complex synthesis, potential immunogenicity, and maintaining stable binding between glycan ligands and lysosomal receptors. The efficiency of internalization depends heavily on the density and position of mannose 6 phosphate conjugation, while the antibody component must balance target selectivity with in vivo stability and half-life.
Technical Limitations and Future Perspectives
Current PROTAC research is constrained by the limited repertoire of E3 ligases (mainly CRBN and VHL), restricted multi-target flexibility, and challenges in stabilizing ternary complexes. LYTAC technology faces hurdles such as cell-type variability in lysosomal receptor expression, strong antibody dependence, and a lack of generalized ligand frameworks.
Future innovation directions include:
-
Development of alternative degradation routes beyond ubiquitination (e.g., AUTAC, ATTEC);
-
Construction of universal linker and ligand libraries;
-
Implementation of AI-driven molecular design to accelerate discovery;
-
Integration of targeted protein degradation with complementary modalities such as immunotherapy and RNA interference.
Comparison Summary: Key Differences Between PROTAC and LYTAC
|
Feature |
PROTAC |
LYTAC |
|
Degradation pathway |
Ubiquitin proteasome system |
Endocytosis lysosome pathway |
|
Target type |
Intracellular proteins |
Membrane and secreted proteins |
|
Molecule type |
Small molecule |
Antibody or ligand conjugate |
|
Recruiter |
E3 ligase such as VHL or CRBN |
Lysosomal receptor such as CI M6PR |
|
Key challenges |
Ternary complex stability, permeability, bioavailability |
Immunogenicity, conjugation efficiency, receptor variability |
MtoZ Biolabs: Empowering Protein Degradation Research
MtoZ Biolabs provides a comprehensive platform for protein degradation studies, combining proteomic analysis with mechanistic validation:
-
Employs TMT, DIA, and PRM-based quantitative proteomics to accurately measure dynamic protein abundance changes before and after degradation;
-
Utilizes Co-IP and pull-down assays to assess ternary complex stability;
-
Conducts ubiquitination profiling and receptor expression analyses to guide degrader system design;
-
Offers mechanistic tracing, cellular model development, and multi-omics data integration for comprehensive project support.
Conclusion
PROTAC and LYTAC technologies represent two foundational and complementary paradigms of targeted protein degradation, operating through proteasome-based and lysosome-based pathways, respectively. Their combined application enables modulation of intracellular, extracellular, and membrane-associated proteins, greatly expanding the range of the druggable proteome. Although both platforms continue to evolve, their potential in precision medicine is increasingly evident. With continuous advances in proteomics, structural biology, and AI-driven modeling, targeted protein degradation is poised to become a transformative driving force for next-generation therapeutics.