PROTACs

What are PROTACs?

Also known as protein degraders, PROTACs aim to eliminate a target protein using a cell’s own waste disposal mechanisms. This is different from molecules that inhibit or block the protein. Instead, they remove the protein from the cell by tagging it for destruction. In order to do this, an E3 ligase must bind to the target protein. E3 ligases are proteins involved in the waste disposal system of the cell. This will create a three-part complex that causes the protein to be covered in the ubiquitin, which sends it to the proteasome for degradation.  

How do PROTACs Work?

1. A PROTAC enters the cell.

2. The PROTAC either binds to the target protein or the E3 ligase.

3. The other protein binds, which creates a three-part complex.

4. The target protein gets covered in ubiquitin.

5. The proteasome destroys the target.

6. The PROTAC is released and can be used again.

Challenges in Development of PROTACs

SincePROTACs have three parts to them – including an E3 ligase binder, a linker, and a target binder – there are many possible combinations available. This requires a lot of synthetic and hands-on work in the lab. Testing them can also take a lot more work than testing inhibitors because there are many factors that scientists must evaluate. This includes protein binding, the shape and formation of the complex, cell permeability, degradation in cells, and cooperativity. Choosing the right E3 ligase is also tedious. There are 600+ possible ligases in human cells, and not every one works for every target. It takes a lot of trial and error to choose a fitting E3 ligase, and this can determine if degradation happens or not.

Benefits of PROTACs

PROTACs are unique because they can turn a gene off without editing a genome. This function is both controlled and reversible. You can add a PROTAC to turn a gene off, then remove it so that it can return to its original state. Protein degraders are also helpful because they do not need to block a functional site; they only need a binder to bring the E3 ligase to the target protein. Given thatPROTACs can act catalytically, they work in low concentrations and lead to an amplified response. This can also limit possible side effects from the PROTACs.

References:

Békés, Miklós, et al. “PROTAC Targeted Protein Degraders: The Past Is Prologue.” Nature Reviews Drug Discovery, vol. 21, no. 3, 18 Jan. 2022, pp. 1–20, www.nature.com/articles/s41573-021-00371-6, https://doi.org/10.1038/s41573-021-00371-6.

Ciulli, Alessio, and Nicole Trainor. “A Beginner’s Guide to PROTACs and Targeted Protein Degradation.” The Biochemist, vol. 43, no. 5, 23 July 2021, https://doi.org/10.1042/bio_2021_148.

Liu, Zi, et al. “An Overview of PROTACs: A Promising Drug Discovery Paradigm.” Molecular Biomedicine, vol. 3, no. 1, 20 Dec. 2022, link.springer.com/article/10.1186/s43556-022-00112-0, https://doi.org/10.1186/s43556-022-00112-0.

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