Table 1.

PIP degradative approaches.

PIP Degradative Approach	Concept	Limitations	Target Proteins Tested Relevant for NDs
Molecular glues (MGs)	Small molecules able to stabilize the interaction between an E3 ligase and a POI, leading to POI polyubiquitination and degradation.	Lack of rational design for novel molecules.	GRB2
PROTACs	Heterobifunctional molecules that put in close proximity a target POI and an E3 ligase, triggering POI ubiquitination and degradation by the proteasome.	Molecules with poor drug-like profile. Lack of well-developed ligands to exploit different E3 ligases.	Tau, α-synuclein, TDP-43, GSK-3β, LKRR2, Htt
SNIPERs	Bivalent degraders (same as PROTACs) that use a specific E3 ubiquitin ligase: IAP E3 ligase.	Unique E3 ligase used. Additionally, molecule absorption, distribution, metabolism, excretion, and toxicity have not been properly assessed.	Htt
AUTACs and ATTECs	Bivalent (AUTACs) or monovalent (ATTECs) degraders that trigger protein degradation through the autophagy/lysosomal pathway.	Lack of understanding about the mode of action and potential off-target effects provoked by hijacking the lysosomal pathway.	Tau, α-synuclein, Htt
Chaperone-mediated autophagy (CMA) molecules	Protein degradation mediated via the Hsc70 chaperone that can interact with LAMP2A and transfer the target POI into the lysosomal cavity to induce POI degradation.	Low molecule stability and poor molecule delivery efficiency.	Htt, α-synuclein, Aβ aggregates
Hydrophobic tags (HyTs)	Hydrophobic tags attached to POIs can mimic the state of misfolded proteins, leading to POI degradation.	Poor biological activity that seems to depend on the length and composition of the hydrophobic tag. New tags and better understanding of the mechanism of action are needed.	Tau, TDP-43