Proteolysis targeting chimera (PROTAC®) is a new and promising technology that utilizes the ubiquitin‐protease system to target a specific protein and induce its degradation in the cell. As a world-leading service provider, Creative Biolabs has successfully established an advanced PROTAC® development platform to target varieties of proteins and thus help global customers’ drug discovery programs.
Estrogen-related receptor alpha (ERRα) is a member of the nuclear receptor superfamily which are modular proteins with distinct DNA binding, activation and ligand-binding domains. It has been reported that ERRα has a role in the regulation of energy metabolism, lipid uptake, fatty acid beta-oxidation, the tricarboxylic acid cycle, and oxidative. Further, ERRα is thought to be involved in bone formation, aromatase and lactoferrin expression in estrogen responsive tissues as well as mitochondrial fatty acid b-oxidation in skeletal muscle and the heart. Studies have shown that the expression of ERRα is ubiquitous and elevated in metabolically active tissues such as the heart, kidneys, intestine, skeletal muscle, brown adipose tissue (BAT) and liver.
During the past years, ERRα has been treated as a target for the development of novel therapeutics to treat numerous diseases, such as breast cancer, type 2 diabetes, and liver metabolic disease. Recently, PROTAC® technology has been used to develop small molecular candidates to target ERRα for degradation.
Fig.1 Structure of estrogen-related receptor alpha.
PROTAC® molecules are composed of three major components, namely a small-molecule ligand for a targeted protein, an E3 ubiquitin ligase recognition motif, and a linker. Once the E3 ligase positioned at the appropriate distance and orientation, the ubiquitinated target protein is subsequently recognized by the proteasome, where it is degraded. ERRα possesses the typical characteristic structural features of nuclear receptors, including a non-conserved amino-terminal domain (NTD), a central zinc finger DNA-binding domain (DBD), and a functional C-terminal ligand-binding domain (LBD). To date, small molecule and peptide-based PROTAC® molecules targeting ERRα have been developed through different methods, including side-chain crosslinking, nucleation and the incorporation of β or γ amino acids.
Fig.2 Proteolysis targeting chimeras (PROTAC®s). (Bondeson, 2015)
PROTAC®s are mainly based on small molecules, while peptide-based PROTAC®s are much less explored, probably due to the poor physiochemical properties of the unmodified peptides, such as low intracellular stability and poor cell permeability. With years of experience and top technology platform, Creative Biolabs is capable of generating numerous ligands with particular or novel characteristics through appropriate strategies, such as structure-based computational methods and phage display based recombinant antibody construction technology. Furthermore, we also offer ligand modification services to transform existing ligands with improved stability and cell permeability for global customers. Working in the field of structural biology and drug discovery, our professional scientists could provide both standard and customized studies to promote your research.
Creative Biolabs is dedicated to accelerating worldwide customers’ project development. We offer ligand design and modification services for global researchers. For more detailed information, please feel free to contact us or directly send us a quote.
Reference
Our customer service representatives are available 24 hours a day, from Monday to Sunday. Contact Us