Targeted protein degradation is an emerging drug discovery strategy that can be used to treat difficult-to-treat diseases. Creative Biolabs is advancing the field of targeted protein degradation, using the body’s inherent protein recycling mechanism to degrade rather than inhibit disease-causing proteins. With our proprietary target protein degradation platform, we are committed to accelerating drug discovery with unparalleled ability to target and degrade the most intractable of proteins, providing new therapeutic strategies for complex diseases.
The proteolysis-targeting chimera (PROTAC®) is a new technology that uses the intracellular ubiquitin-proteasome system to induce the degradation of targeted proteins and has received great attention in the field of targeted therapies. PROTAC® is a bifunctional molecule that recruits a target protein in proximity to an E3 ubiquitin ligase to trigger protein degradation. The basic mode of action of PROTAC® is shown in Fig.1. PROTAC® links together a ligand for the protein of interest (POI) and an E3 ligase binder. The inductive proximity between the ligase and the target protein results in polyubiquitination (Ub) of POI, which triggers its proteasome degradation. The released PROTAC® exerts its function again, which gives rise to a catalytic mode of action.
Fig.1 Mode of action of PROTAC®s. (Scheepstra, 2019)
Sirtuins were originally described as class III histone deacetylases (HDACs) or Sirt2 proteins, forming a very special class of the lysine deacetylases (KDACs) family. Sirtuins use NAD⁺ as a cofactor and constitute the class III KDACs, which can remove acyl groups from the ε-amino group of acylated lysine residues. The human genome encodes seven isotypes of sirtuins (Sirt1-7), all of which have different catalytic activities and subcellular localization. The isotype Sirt2, which is mainly located in the cytoplasm, has been shown to have important effects on cell cycle regulation, autophagy, peripheral myelination, and immune and inflammatory response. In addition, many studies have shown that the overall cellular agenda of Sirt2 is not only dependent on its catalytical activity but also its protein-protein interactions with binding partners, such as KDAC6 and HOXA. The dysregulation of Sirt2 is associated with the pathogenesis of bacterial infections, neurodegenerative diseases, type II diabetes, and cancers, which makes Sirt2 a promising target for pharmaceutical intervention.
The PROTAC® has been widely used to induce the degradation of various proteins including kinases, transcription factors, and epigenetic reader proteins. Sirtuin rearranging ligands (SirReals)-based PROTAC® can induce isotype-selective Sirt2 degradation, resulting in the hyperacetylation of the microtubule network coupled with enhanced process elongation. Therefore, SirReal-based PROTAC® is able to chemically induce the degradation of an epigenetic eraser protein.
Creative Biolabs' experienced experts have developed a proprietary protein degradation platform designed to increase the efficiency of target protein degradation and develop new therapies for previously undruggable diseases. Our PROTAC® platform includes informatics-driven target recognition, novel E3 ligase, proprietary ternary complex predictive modeling capabilities, and biological evaluation tools. Based on our powerful protein degradation platform, Creative Biolabs provides ligand design services for SIRT2, including several different forms, such as small molecules, peptides, proteins, as well as antibodies.
Creative Biolabs offers our clients a variety of modules covering all aspects of PROTAC® services, from molecular discovery, ligand design, linker optimization, to biological evaluation. For more details about PROTAC® services, please feel free to contact us.
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