ATTEC (autophagosome-tethering compounds) is a novel target protein degrade strategy that based on the macroautophagy/autophagy pathway. In eukaryotic cells, macroautophagy/autophagy is a bulk degradation system that engulfs proteins into phagophores and induces subsequent autophagic degradation process. Without involving complicated enzymatic reactions, ATTEC has attracted scientist’s attention on diseases related proteins degradation and drug discovery.
In contrast to PROTAC and AUTAC, ATTEC molecules are independent of ubiquitination, which based on LC3 protein. LC3 is a crucial protein in the autophagy pathway, in which LC3 protein conjugated to phosphatidylethanolamine to form LC3-phosphatidylethanolamine conjugate (LC3-II), which is recruited to autophagosomal membranes. Based on this principle, ATTECs are designed by interacting with both the target protein and the autophagosome protein LC3, tether target protein to autophagosomes for subsequent autophagic degradation without influencing autophagy activity per se.
Figure 1 The concept of ATTECs.
Neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, are associated with the formation of protein aggregates/oligomers by misfolded proteins. Molecules with high lipid solubility and under 500 kDa molecular weight may be more necessary for likely crossing the blood-brain barrier via passive diffusion. Study has showed that one of the ATTEC molecules reduced mutant huntingtin protein aggregates significantly which providing entry points to new treatment strategies of neurodegenerative diseases.
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