After PROTAC: Looking forward to a breakthrough in lysosomal degradation technology

Targeted protein degradation (TPD) technology uses two naturally occurring protein degradation systems in cells, namely Ubiquitin-proteasome system (UPS) and lysosomal degradation pathways to achieve disease-related The specific and efficient degradation of protein can achieve the effect of disease treatment.

The difference between ubiquitination-proteasome system (UPS) and lysosomal degradation pathway

Source: Kailaiying, Biological Jingwei, Yingdi Capital

The lysosomal degradation pathway is mainly based on two pathways: endocytic vesicles and autophagy: based on endocytic vesicles, a targeted chimera system (Lysosome targeting chimaeras, LYTACs) is established; based on autophagy, including autophagy mediated by chaperone (Chaperone-mediated autophagy, CMA), Autophagy-Targeting Chimera (Autophagy-Targeting Chimera, AUTAC), and Autophagosome-tethering compound (ATTEC).

Schematic diagram of the mechanism of action of the lysosomal degradation pathway

Source: Literature [5]

The technical differences between them (LYTAC, CMA, AUTAC, ATTEC, etc.

Source: Kailaiying, Biological Jingwei, Yingdi Capital

Research situation

1.

Picture source: Literature [1]

In their research, oligomannose-6-phosphate (M6Pn) was covalently cross-linked to the specific antibody of the target protein.

2.

Image source: I love biochemical public account

Fan et al.

3.

Picture source: Literature [3]

However, the autophagy process has many steps and is extremely complicated, and there will be many influencing factors, so the stability is poor.

4.

Picture source: Literature [4]

Outlook

In recent years, CMA, LYTAC, ATTEC, and AUTAC degradation methods based on lysosomal degradation pathways that have emerged in recent years have provided us with new ideas in the degradation of target proteins, and further expanded the range of target proteins of TPD drugs.

references

[1] Banik SM, Pedram K, Wisnovsky S, etal.

[2] Fan XL, Jin WY, Lu J, et al.
Rapid andreversible knockdown of endogenous proteins by peptidedirected lysosomaldegradation.
Nat Neurosci, 2014,17(3): 471-480.

[3] Takahashi D, Moriyama J, Nakamura T, etal.
AUTACs: cargo-specific degraders using selective autophagy.
Mol Cell, 2019,76(5): 797-810.
e10.

[4] Li ZY, Wang C, Wang ZY, et al.
Allele-selective lowering of mutant HTT protein by HTT-LC3 linker compounds.
Nature, 2019, 575(7781): 203-209.

[5]Chen SP, Yang H, Jiang JL, et al.
Researchprogress on targeted protein degradation technology and its applications indiseases therapy.
Chin J Biotech, 2021, 37(12): 1-18.