Natural product-based PROteolysis TArgeting Chimeras (PROTACs)

Covering: upto 2022Natural products have an embedded recognition of protein surfaces. They possess this property as they are produced by biosynthetic enzymes and are substrates for one or more enzymes in the biosynthetic pathway. The inherent advantages, compared to synthetic compound libraries, is this ligand-protein binding which is, in many cases, a function of the 3-dimensional properties. Protein degradation is a recent novel therapeutic approach with several compounds now in the clinic. This review highlights the potential of PROteolysis TArgeting Chimeras (PROTACs) in the area of natural products. The approach will complement existing approaches such as the direct use of a bioactive natural product or its analogues, pharmacophore development and drug-antibody conjugates. The chemical synthesis and challenges of using natural product-based PROTACs are summarised. The review also highlights methods to detect the ternary complexes necessary for PROTAC mechanism of action.