Ligand Design for Tau-targeting PROTAC^®

For many years, Tau has been a key target for therapeutic intervention for the development of disease-modifying therapies. With the emerging of new targeted protein degradation by proteolysis targeting chimeras (PROTAC^®s), Tau-targeting PROTAC^® has emerged as a promising strategy for the drug discovery of related diseases. Creative Biolabs is a leading product manufacturer and service provider in the PROTAC^® space. With an unrelenting drive in ligand research and the PROTAC^® industry, Creative Biolabs is executing our strategies to bring comprehensive Tau-binding ligand design services to our clients.

Introduction of Tau

Tau protein, a microtubule-associated protein, is predominantly expressed in the neurons. In humans, Tau is encoded by the 16 exons-comprising microtubule-associated protein Tau (MAPT) gene on chromosome 17q21. Because of the alternative splicing of exons 2, 3, and 10, six major Tau isoforms are expressed in the human brain.

Fig.1 Organization of the Tau gene, and isoforms of the Tau protein. (PIRSCoveanum, 2017)

Tau plays an important role in the stabilization of microtubules, which are important cytoskeleton scaffolds for the cells and support cellular trafficking. Besides, Tau is related to deficiencies in oxidative phosphorylation or apoptotic activity. A consequence of these deficiencies is the appearance of mitochondrial fragmentation. Almost 80 diseases caused by missense mutations and intronic mutations in the Tau gene have been found in familial cases of frontotemporal dementia (FTD). Hyperphosphorylated Tau accumulates with ubiquitin in aging neurons as the neurofibrillary tangles. In Alzheimer's disease (AD), neurofibrillary tangles composed of hyperphosphorylated Tau and ubiquitin complexes are more widespread and more numerous.

Fig.2 Process of Tau tangle formation during AD progression. (Kumar, 2018)

Tau-targeting PROTAC^®

PROTAC^® protein degraders recruit an E3 ligase to tag the target protein with ubiquitin, which directs its degradation through the proteasome. As the target protein is degraded, the PROTAC^® protein degrader is released and acts iteratively to destroy additional target protein. Studies reported that using PROTAC^®s to recruit KEAP1 to induce the degradation of Tau shows a promising character in the treatment of AD. A KEAP1-Tau fused peptide PROTAC^® appended with a poly-D-Arg showed strong in vitro binding to KEAP1 and Tau with decent cell permeability. Further western blotting (WB) and flow cytometry confirmed time- and concentration-dependent degradation of Tau. The results suggested that Tau can be degraded via KEAP1 dependent ubiquitination using PROTAC^®s, and this approach holds promise as a strategy in the treatment of neurodegenerative diseases.

Fig.3 Schematic diagram of Tau-targeting peptide PROTAC^®. (Lu, 2018)

Ligand Design Services at Creative Biolabs

Based on our advanced design strategies, a series of Tau protein binding moieties, as well as multifunctional PROTAC^®s, have been designed by Creative Biolabs. The ligands designed by Creative Biolabs can be different forms, such as small molecules, antibodies, and peptides. We also provide different E3 ligase binding ligands to induce Tau degradation and therefore prevent cytotoxicity. For instance, the combination could be the Tau recognition sequence and VHL E3 ligase binding part or Tau recognition sequence and KEAP1 E3 ligase binding ligand.

Advantages

• Show strong in vitro binding ability with Tau
• Better cell permeability
• Downregulate the intracellular Tau level in both time- and concentration-dependent manner
• Promote the KEAP1-dependent poly-ubiquitination and proteasome-dependent degradation of Tau

Creative Biolabs has years of experience in antibody engineering, ligand discovery and compound synthesis. Our experts will help you make new progress in your drug discovery development. If you are interested in our ligand design for Tau-targeting PROTAC^®, please feel free to contact us for more information.

References

1. PIRSCoveanu, D. F. V.; et al. Tau protein in neurodegenerative diseases-A review. Rom. J. Morphol. Embryol. 2017, 58: 1141-1150.
2. Kumar, K.; et al. Recent advances in the neurobiology and neuropharmacology of Alzheimer’s disease. Biomedicine & pharmacotherapy. 2018, 98: 297-307.
3. Lu, M.; et al. Discovery of a KEAP1-dependent peptide PROTAC^® to knockdown Tau by ubiquitination-proteasome degradation pathway. European journal of medicinal chemistry. 2018, 146: 251-259.