Proteolysis-targeting chimera (PROTAC^®) has become a promising and appealing technology for modulating a protein of interest (POI) by degradation due to its unique features. Based on the deep understanding of various regulatory proteins and our advanced PROTAC^® development platform, Creative Biolabs is a leading service provider that offers ligand design services of regulatory proteins for our global customers.

Background

The regulatory proteins often respond to small signal molecules making the protein conformation active or inactive by changing its ability to bind DNA. These proteins, including transcription factors to regulate which genes to turn on under any particular conditions, help control the synthesis, activity, stability, localization, or degradation of proteins in cells. Some of the regulatory proteins often bind DNA and prevent gene expression when the small-signal molecule (the inducer) is absent. Transcription factors as regulatory proteins are considered to be the most diverse and vital mechanism of gene regulation and play essential roles in maintaining homeostasis in the body.

PROTAC^® is a small molecule consisting of a targeting ligand for a target protein, an E3 ubiquitin ligase recruitment ligand, and a chemical linker connecting the two ligands. Upon PROTAC^®-mediated heterodimerization of the bound proteins, the target protein is ubiquitinated and degraded by the proteasome. Many PROTAC^®s have been developed to recruit E3 ubiquitin ligases to substrate using high-affinity ligands for the target proteins. Nowadays, targeted protein degradation using PROTAC^® has emerged as a novel therapeutic modality in drug discovery.

Fig.1 Mode of action of PROTAC^®s. (Sun, 2019)

Novel Ligand Design for Regulatory Proteins PROTAC^®

Regulatory proteins determine when genes are switched on and off, and about a thousand transcription factors with different functions are known, such as CRABP-I and II (cellular retinoic acid-binding protein I and II), TACC3 (transforming acidic coiled-coil containing protein 3), AHR (aryl hydrocarbon receptor), FKBP12 (FK506 binding protein 12), ERRα (estrogen-related receptor α), and X-protein.

Based on our perfect combination of sophisticated technologies and the PROTAC^® development platform, scientists at Creative Biolabs can generate various kinds of ligand and endow them with particular or novel characteristics through appropriate strategies. Depending on the types and structure of the specified regulatory proteins and the specific generation strategies, these novel ligands take many different forms. They include small molecules with structure-based computational methods for in silico screening, peptides and recombinant antibodies based on phage display technology. In this situation, high-throughput techniques to screen a large of ligand compounds for PROTAC^® formation could be employed and make these ligands recruit E3 ubiquitin ligases to target regulatory proteins.

Ligand Modification for Regulatory Proteins PROTAC^®

It may still be a big challenge for designing new on-target PROTAC^®s, thus, Creative Biolabs can also provide existing ligand modification and engineering against targets in this situation. The functional ligand molecules are rationally designed and prioritized based on their ability to induce favorable contacts and allow the cooperative formation of a stable complex between the E3 ligase and the target.

Along with our extensive experience in PROTAC^® development, Creative Biolabs is committed to designing ligands for a variety of targets for our customers all over the world. If you are interested in our service, please do not hesitate to contact us for more details.

Reference

1. Sun, X.; et al. PROTAC^®s: great opportunities for academia and industry. Signal Transduction and Targeted Therapy. 2019, 4(1): 1-33.