AUTAC

Recently, the promoters specifically degrading a protein using intracellular degradation are attracting attentions. The major intracellular degradation mechanisms include ubiquitin-proteasome system (UPS) and macroautophagy/autophagy. PROTACs is an UPS based small-molecule degraders that connect a ubiquitin ligase with the substrate and thereby promote target protein ubiquitination. Rely on autophagy, AUTAC (autophagy-targeting chimera) degrades a wider range of substrates by triggering K63 polyubiquitination, especially suitable for degrading target proteins in cytoplasm that are resistant to PROTAC molecule.

Figure 1 The concept of AUTACs.

As a heterobifunctional compound, AUTAC is composed of a target-specific binder, a flexible linker, and a tag (guanine derivatives) that recruits the autophagy system. After penetrating cell membranes, the chimeric molecule delivers the degradation tag to a target protein of interest by its binder.

AUTAC provides a new modality for research on autophagy-based drugs. With the target proteins forming the autophagosomes, the autophagy receptors such as SQSTM1/P62 recognize Lys63 (K63) polyubiquitinated target proteins and transfer them to autophagosomes for degradation. It had been reported that the AUTAC molecule was successfully used in degradation the target protein as well as organelles, for instance, damaged mitochondria.

Profacgen can provide a complete set of technical services, from AUTAC design and synthesis, to the functional assay, and help our customer study in autophagy-based drugs discovery. Profacgen is keen to communicate and cooperate with our clients on the design and application of AUTACs. Please feel free to contact us for details.

Reference

1. Takahashi, D., Moriyama, J., Nakamura, T., Miki, E., Takahashi, E., Sato, A., Akaike, T., Itto-Nakama, K, Arimoto, H. (2019). AUTACs: Cargo-Specific Degraders Using Selective Autophagy. Molecular Cell. doi: 10.1016/j.molcel.2019.09.009