Ligand Screening for VHL-based PROTAC

With more than 10 years of experience in the development of small molecule drugs, Creative Biolabs has accumulated abundant successful experience and in-depth research on PROTAC technology. Till now we can confidently provide comprehensive professional and efficient related services to help researchers to fuel the development of PROTAC-based therapeutics.

Introduction to VHL

VHL (Von Hippel-Lindau), also known as Von Hippel-Lindau tumor suppressor, is an E3 ligase that participates in the ubiquitination and degradation of HIF1α (hypoxia inducible factor 1α) protein. Under normal physiological conditions, VHL can recognize and bind HIF1α only when the two proline residues in HIF1α are hydroxylated in the presence of oxygen. Under hypoxic conditions or when the VHL gene is mutated, VHL cannot bind HIF1α. In this case, HIF1α will dimerize with HIF1β and activate transcription of genes like VEGF (vascular endothelial growth factor), PDGF (platelet-derived growth factor B), EPO (erythropoietin), and genes that involve in glucose uptake and metabolism.

The VHL gene mutation is related to the occurrence of Von Hippe-Lindau disease, a rare multisystem genetic disease. The disease is more serious and fatal, and the average life expectancy of patients with VHL syndrome generally does not exceed 49 years. The main causes of death are rupture and bleeding of central nervous system hemangioblastoma, renal cell carcinoma and malignant hypertension caused by pheochromocytosis.

Typical distribution of hemangioblastomas in Von Hippel-Lindau disease and the heredity pattern of the disease. Fig.1 Typical distribution of hemangioblastomas in Von Hippel-Lindau disease and the heredity pattern of the disease.

Ligand Design for VHL-based PROTAC

E3 ligase is a large protein family with more than 600 members. As one of them, VHL also gained a lot of attention to the development of PROTAC. VHL can form a complex with elongation protein C, elongation protein B, Cul2, and Rbx1 to form E3 ubiquitin-protein ligase, in which VHL can be used as a substrate recognition subunit. The β domain of VHL has about 100 amino acids, containing an amino-terminal multi-chain β sandwich and a carboxy-terminal α helix close to one of the β chains through hydrophobic interaction. The β sandwich forms a partially exposed hydrophobic core that, along with other polar residues, provides a binding site for the hydroxylated proline peptide-containing ligand. Contact residues in the VHL β domain are highly conserved among human, fly, frog, and worm VHL homologs.

Structure of VHL. Fig.2 Structure of VHL.

Applying experience in small molecule drug screening and design, the experts of Creative Biolabs studied the structure of VHL and its interaction with HIF1α, and used fragment screening to find a satisfactory starting point for drug design of VHL ligands. Based on these studies, researchers designed some ligand compounds starting from the HIF1α peptide structure, and prepared the corresponding PROTAC molecules, achieved pleasing results in terms of effect evaluation. Continuing to study along this proven and feasible strategy, and designing VHL ligands from various forms such as small molecules, peptides, and even antibodies, and further studying the interaction rules between VHL and ligands to screen more ligands, as well as optimizing existing ligand molecules, are what Creative Biolabs has always been doing down-to-earth and are what we can provide to researchers around the world.

Advantages

  • World-leading research and development team in drug development and PROTAC technology
  • Excellent expert team with a background in small molecule drugs, peptide drugs, and antibody development
  • Abundant PROTAC-based drug development experiences
  • Well-trained laboratory personnel, advanced equipment, complete laboratory, and workshop
  • One-stop service system from PROTAC design to production to evaluation

Creative Biolabs has long-term devoted to the development of PROTAC. Our scientists are confident in offering the best and most suitable ligand design for our customers all over the world. If you are considering developing novel PROTACs against the target of interest, please do not hesitate to contact us for more details.

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