PROteolysis TArgeting Chimeras (PROTACs) Technology

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1) What is the technology, how does it work? PROteolysis TArgeting Chimeras (PROTACs) is an effective technology that targets protein degradation (Sun et al., 2019). Target protein degradation is the process of aiming a disease-causing protein for destruction. Each PROTAC contains three major components collectively known as heterobifunctional molecules (Gao et al., 2020). They include a protein-of-interest (POI) ligand, an E3 ligase ligand, and a linker (Gao et al., 2020). These components can hijack the intracellular inherent ubiquitin-proteasome system to degrade different POIs (Konstantinidou et al., 2019). PROTACs work by inducing selective intracellular proteolysis instead of acting as a conventional protein inhibitor (Pei et al., 2019). It takes advantage of the cell’s waste disposal system that eliminates unwanted proteins.
The Proteasome system helps the cell remove unwanted or damaged proteins and recycle their building blocks to produce new proteins (Pettersson, 2019). This system plays a significant role in cell growth, cellular stress management, and the immune system. One end of the molecule binds to the targeted proteins, while the other binds to the ubiquitin ligase, which then marks the targeted protein for destruction (Zou et al., 2019). This notifies the cell’s proteasome that this particular protein can be damaged. This process co-opts the body’s frequently occurring mechanisms to damage disease-causing proteins (Sun et al., 2019). 2) Who discovered it? How was it discovered?American scientists Craig Crews, Ray Deshaies, and Kathleen Sakamoto discovered PROTACs technology in 2001 by studying controlled proteostasis like the pharmacological modulation of protein turnover (Konstantinidou et al., 2019). Crews and his team later developed PROTACs technology to induce proteolysis. They found that PROTACs can allow pharmacological targeting of earlier thought ‘‘undruggable’’ proteins responsible for cancer drug resistance (Cecchini et al., 2021). The excitement around the study attracted public and private investment in therapeutic methods based on targeted protein degradation. Before working on this technology, the Crews lab’s synthesis and mode of action studies of epoxomicin found that PROTAC is a potent and selective proteasome inhibitor (Gao et al., 2020). Ensuring medical chemistry efforts resulted in the production of the epoxyketone-containing proteasome inhibitor YU101, which acts as the foundation of the multiple myeloma drug Carflzomib (Pettersson, 2019).
In one of the first proof-of-concept experiments published in 2001, Crews Labs and collaborator Ray Deshaies reported the first bifunctional molecules of PROTACs technology based on short peptides. Their discovery led to the first-generation PROTACs. However, the activity of these peptides PROTAC is low and still plays within the micro molecular range. Thus, the primary obstacle could be the poor cell permeability of the peptide technology platform. Fortunately, continuous attempts to improve the technology have led to the devel...