Recently, many remarkable reviews on Proteolysis Targeting Chimeras (Protein Degraderss) have appeared in drug discovery and development. This tool takes advantage of the intracellular ubiquitin-proteasome system (UPS) to ubiquitylate and selectively degrade target proteins. Cellular metabolism involves a series of biochemical reactions that occur in living organisms to maintain life. Metabolic enzymes are a class of enzymes regulating metabolic pathways in energy homeostasis, including glucose, lipid biosynthesis, fatty acid, and amino acid metabolisms. With advanced technologies and abundant experience in Protein Degraders development, Creative Biolabs focuses on the current state of protein degradation research and provides ligand design services for Protein Degraderss development.

• The Role of Metabolic Enzymes

Metabolic enzymes carry out a number of cellular physiological functions necessary for survival and homeostasis. There’re many protein types of metabolic enzymes that encompass oxidoreductases, carboxylases, dehydrogenases, lipoxygenases, transferases, kinases, lyases, and others. Some enzymes contribute to breaking down large nutrient molecules (e.g. fats, proteins, and carbohydrates) into small molecules. Enzymes can also implement numerous other functions, including the release and storage of energy, the course of respiration, and vision.

Abnormal regulation of metabolic pathways has been associated with diabetes, hypertension, osteoporosis, hormonal imbalances, cancers, and many other disorders. There’re hundreds of inherited metabolic diseases caused by varying genetic defects, such as Phenylketonuria (PKU), Gaucher disease, and Wilson's disease. Most patients with metabolic disorders have a defective gene resulting in a corresponding enzyme deficiency. As such, these enzymes can be potential therapeutic targets for the treatment of metabolic disturbances.

Fig.1 Multifaceted regulation in cancer stem-like cells (CSCs) involving enzymes. (Dong, 2017)

• Rational Ligand Design Services at Creative Biolabs

The innovations in the field of targeted protein degradation and manipulation of the UPS create rapid and efficient therapeutic approaches for metabolic disorders. Protein Degraderss are a panel of bivalent ligands in which a compound that binds to the target protein is linked to the second molecule that binds an E3 ubiquitin ligase through a linker. At Creative Biolabs, there’re various types of E3 ligases, including Von Hippel-Lindau (VHL), cereblon (CRBN), mouse double minute 2 homolog (MDM2), cellular inhibitor of apoptosis (cIAP) that have been applied in Protein Degraders technology.

Fig.2 Chemical structures of all-small-molecule Protein Degraderss. (Gu, 2018)

Targeting metabolic enzymes is of high interest in drug discovery for a variety of metabolic disorders. At Creative Biolabs, our groups take into consideration whole aspects of enzyme chemistry, enzyme structure, and metabolite structure, leading to the enhanced understanding of metabolism and improved capacity to predict enzyme function and metabolic pathways. We exploit the role of ternary complex formation in Protein Degraders design and offer professional ligand design services for various cellular metabolic enzymes. According to different types of enzymes, our skillful platforms including but not limited to:

• Ligand Design for MetAP-2-targeting Protein Degraders

Methionine aminopeptidase-2 (MetAP-2) is a class of metalloproteases that plays a key role in protein maturation as catalyzing the removal of initiator methionine (Met) residue from nascent proteins. We offer custom services to design multiple ligands for the MetAP-2 enzyme based on its structural properties.

• Ligand Design for DHODH-targeting Protein Degraders

Dihydroorotate dehydrogenase (DHODH) is a ubiquitous flavin mononucleotide (FMN) flavoenzyme and the fourth enzyme implicated in the de novo pyrimidine nucleosides biosynthetic pathway. We’d like to provide Protein Degraders-based protein degradation services for the formation of valid and sustained DHODH ligands.

• Advantages
  • End-to-end solutions for ligand design services targeting various metabolic enzymes within cells
  • Protein Degraders-based protein degradations allow for rapid and sustained inhibition of downstream signaling
  • Seasoned specialists with rich experience in Protein Degraders development projects
  • Superior after-sale services to protect clients’ rights and interests

The life-sustaining pathways performed by metabolic enzymes are essential for the growth and maintenance of cellular integrity. As a famous company in the biotechnical industry, Creative Biolabs has launched a diversity of ligand design strategies for metabolic enzymes and also provides custom Protein Degraders services targeting other proteins as required. Diverse modalities of ligands can be developed in your challenging projects, including small molecules, peptides, antibodies, and proteins. If you’re interested in our services, please don’t hesitate to contact us or directly send us an inquiry.

References

1. Dong, B.W.; et al. Metabolic enzymes: key modulators of functionality in cancer stem-like cells. Oncotarget. 2017, 8(8): 14251-14267.
2. Gu, S.; et al. Protein Degraderss: an emerging targeting technique for protein degradation in drug discovery. BioEssays. 2018, 40(4): e1700247.