Proteolysis-Targeting Chimeras, or PROTACs, represent an innovative class of therapeutic molecules designed to address diseases by removing specific proteins from the body. These compounds function by hijacking the cell’s natural protein degradation machinery. Rather than merely blocking a protein’s activity, PROTACs induce its complete elimination. This approach offers a distinct strategy for drug development, aiming to clear disease-causing proteins that contribute to various conditions.
How PROTACs Work
PROTACs are designed as heterobifunctional molecules, meaning they have two distinct active ends connected by a chemical linker. One end of the PROTAC molecule is engineered to bind specifically to the target protein that needs to be degraded. The other end binds to an E3 ubiquitin ligase, a type of enzyme naturally present in cells.
The core mechanism relies on the cell’s ubiquitin-proteasome system (UPS), which is responsible for recycling unwanted or damaged proteins. When a PROTAC enters a cell, it acts as a bridge, bringing the target protein and the E3 ubiquitin ligase into close proximity. This induced proximity is crucial for the subsequent steps.
Once the target protein and the E3 ligase are brought together, the E3 ligase attaches multiple ubiquitin tags to the target protein. Ubiquitin is a small protein that acts like a flag, marking the target protein for destruction. This process, called ubiquitination, involves a cascade of three enzymes: E1 (ubiquitin-activating enzyme), E2 (ubiquitin-conjugating enzyme), and E3 (ubiquitin ligase).
After the target protein is tagged with a chain of ubiquitin molecules, it is recognized by the 26S proteasome. The proteasome acts as the cell’s “waste disposal system,” engulfing and breaking down the ubiquitinated protein into smaller peptides and amino acids. The PROTAC molecule is not consumed in this process.
Beyond Traditional Drug Approaches
PROTACs operate on a fundamentally different principle compared to traditional small molecule drugs, which typically function as inhibitors. Traditional inhibitors work by binding to and blocking the activity of a target protein, often by occupying an active site. This is an “occupancy-driven” mechanism, where a continuous presence of the drug is required to maintain the inhibitory effect.
In contrast, PROTACs initiate an “event-driven” mechanism by inducing the complete degradation of the target protein. Instead of merely inhibiting a protein’s function, PROTACs remove it entirely from the cell. This means that all functions associated with the protein, including enzymatic, scaffolding, or regulatory roles, are eliminated.
A significant advantage of PROTACs is their catalytic nature. A single PROTAC molecule can facilitate the ubiquitination and degradation of multiple copies of a target protein because it is recycled after each degradation event. This contrasts with traditional inhibitors, where each drug molecule typically binds to and inhibits only one target molecule at a time. This catalytic activity means PROTACs can achieve profound effects at much lower concentrations compared to inhibitors.
This distinct mechanism also allows PROTACs to target proteins previously considered “undruggable” by conventional methods. Many disease-causing proteins lack a well-defined active site or a deep binding pocket that traditional small molecules can occupy. PROTACs, however, only need to bind to any accessible surface crevice on the target protein to bring it into proximity with an E3 ligase, expanding the range of potential therapeutic targets.
Diseases Targeted with PROTACs
PROTAC technology is being extensively explored across various disease areas, with significant focus on cancer. In oncology, PROTACs are designed to degrade oncogenic proteins that drive tumor growth and survival. For instance, PROTACs targeting the androgen receptor (AR) and estrogen receptor (ER) are currently in clinical trials for prostate and breast cancer treatment, respectively.
Beyond cancer, PROTACs show promise in addressing neurodegenerative diseases, where the accumulation of misfolded or aggregated proteins is a hallmark. Researchers are investigating PROTACs to degrade proteins like alpha-synuclein in Parkinson’s disease and Tau protein in Alzheimer’s disease, with the goal of clearing these toxic aggregates and potentially slowing disease progression.
The application of PROTACs also extends to viral infections. By targeting and degrading key viral proteins or host proteins essential for viral replication, PROTACs can disrupt the viral life cycle. Examples include research into PROTACs against influenza virus neuraminidase and proteins involved in human cytomegalovirus replication, offering a novel strategy to combat infectious diseases.
Advantages of Protein Degradation
The unique mechanism of protein degradation offers several compelling benefits over traditional protein inhibition. One significant advantage is the potential to overcome drug resistance. Many traditional inhibitors face challenges as target proteins mutate, altering their binding sites and reducing drug effectiveness. By completely eliminating the protein, PROTACs can bypass these resistance mechanisms that rely on changes to an active site.
Protein degradation also leads to a more sustained and complete knockdown of target protein levels. While inhibitors require continuous presence to maintain their effect, the catalytic nature of PROTACs means that even after the PROTAC molecule is cleared, the target protein levels remain low until new protein synthesis occurs. This can translate to less frequent dosing and potentially a longer-lasting therapeutic effect.
The ability of PROTACs to degrade proteins at sub-stoichiometric concentrations due to their catalytic action means that lower effective doses may be possible. This could lead to reduced off-target effects and improved safety profiles compared to drugs that require high concentrations for sustained occupancy.