Chaperone-Mediated Autophagy Protein Degradation Technology (CHAPTAC)

Targeted protein degradation has the potential to unlock a large number of targets that are considered "undruggable," by traditional drug discovery methods. This presents a significant opportunity for developing new therapeutics by destroying the disease-causing proteins through specific techniques.

We have developed a proprietary protein degradation platform that overcomes the current limitations of existing protein degradation approaches. Our proprietary CHAPTAC technology is unique as it reversibly degrades the disease causing proteins via the lysosome or the proteasome degradation machineries of the cell. We have demonstrated that our CHAPTAC technology is more versatile than PROTAC technology in cases where the proteasome is dysfunctional. Since our peptides are made of natural amino acids, they are degraded together with the target protein, and consequently have less toxicity compared with thalidomide-based PROTAC methods of targeted protein degradation. By removing pathogenic proteins from the body, we believe this will lead to more extensive and sustained therapeutic benefits.

Below is a diagram of a non-virally mediated, cell permeable targeting peptide that rapidly and reversibly degrades an endogenous pathological protein through lysosomal degradation or proteasomal degradation.

The Steps in our Technology

The specific protein binding sequence of a target of interest is identified.
The targeting therapeutic degradation peptide is constructed consisting of three parts:
1. a cell-penetrating domain that delivers the specific peptide across the blood-brain barrier and/or the plasma membrane of cells;
2. a short target protein-binding domain that specifically binds to the target protein of interest with high affinity; and
3. a degradation targeting motif which directs the peptide-protein complex for lysosomal degradation or proteasomal degradation.
The therapeutic degradation peptide enters the cell, finds the target disease causing protein, binds to it and drags the target protein to the lysosome or the proteasome for degradation.
The dysfunctional protein together with three additional components – the protein binding domain, the cell penetrating domain and degradation targeting motif are all broken down into their component amino acids and recycled by the cell.

In many cases the lysosome is the preferred degradation pathway rather than the proteasome. The proteasome cannot degrade large aggregated or misfolded proteins. Furthermore, proteasomal dysfunction has been implicated in many neurodegenerative diseases, including Alzheimer's, Parkinson's, and Huntington's diseases, as well as diabetes and various cardiomyopathies. In these disease areas, the lysosome would be preferable for protein degradation. In cases where the lysosome is dysfunctional, we are able to traffic target proteins to the proteasome for degradation.

Almost all other protein degradation platforms are less versatile as they degrade proteins using only one degradation machinery of the cell – either the lysosome or proteasome. We have the ability to use both the degradation machineries of the cell – both the lysosome and the proteasome.

Advantages

Our proprietary CHAPTAC technology offers several key advantages over leading competitive protein degradation techniques, in particular, PROTAC, Antisense Oligonucleotides and siRNA, as well as CRISPR/Cas9.

Characteristics	CHAPTAC	PROTAC	Antisense Oligonucleotide and siRNA	CRISPR/Cas9
Low toxicity	✓	X	X	X
Ease of manufacturing	✓	MAYBE	✓	X
Ease of finding a new molecule	✓	X	✓	✓
Blood-brain barrier and cell permeability	✓	MAYBE	X	X
Targets individual post-translationally modified protein variants	✓	✓	X	X
Rapid protein degradation onset	✓	✓	X	X
Degrades "undruggable" targets	✓	✓	✓	✓
Reversible protein knockdown	✓	✓	✓	X

We have validated our CHAPTAC technology in vitro and in vivo with multiple protein targets in cardiovascular, neurological and cancer indications.