Natural Products in Protein Degradation: Past, Present, and Future
Protein degradation, whether as a PROTAC (proteolysis targeting chimera) or a molecular glue, is an emerging new modality of therapeutic action that has garnered intense interest within the Pharma and Biotech sectors. Historically, plants and natural products have played an outsized role in protein degradation research. For example, much of the early research into the Ubiquitin-Proteasome System (UPS) was conducted with Arabidopsis, a plant that has a full 5% of its genome playing a role in the UPS. In terms of small molecules and their role in protein degradation, examples include the first literature appearance of the term “molecular glue” in 1992 to describe natural product FK-506’s mechanism of action and the elucidation of plant hormone auxin as an E3 ligase ligand. The first PROTAC in fact, utilized the natural product ovalicin, as the protein of interest (POI) warhead. Since then a number of natural products have served as POI warheads, E3 ligase ligands, and molecular glues. Since the UPS is highly conserved across eukaryotes, it’s not surprising that natural products have served, and continue to serve, as a fertile hunting ground for protein degraders.
Figure 1: Example PROTACs utilizing natural product E3 ligase ligand
This fact is highlighted by the recent publication of two reviews centered on natural product-based protein degraders; one from Li et al in Natural Product Reports and the second from Zhenyu et al in Journal of Medicinal Chemistry. The first review focuses on PROTACs and methods to detect the ternary complexes formed between a POI, an E3 ligase, and a PROTAC. The second review covers both natural product-based PROTACs and molecular glues. Examples of natural product-based E3 ligase ligands include nimbolide, bardoxolone, celastrol, and piperlongumine, all plant-based natural products, which have been utilized in PROTACs (Figure 1)As noted by the authors in the J. Med. Chem review, “As a promising direction for the development of PROTACs and molecular glue technologies, natural product-derived degraders warrant extensive exploration in the future. The discovery of new natural ligands of POIs for novel targeted therapeutic strategies and new natural ligands of novel E3 ligases is urgently needed to expand the E3 toolbox for utilization in targeted protein degradation.”
At Enveda, we couldn’t agree more! By utilizing advanced machine learning and AI, our platform overcomes the traditional challenges presented by natural products drug discovery and have brought this proven area into the 21st century. We’re making exciting progress using our platform to find novel natural product ligands to E3 ligases with no known small molecule ligands, molecular glue degraders for “undruggable” targets, and selective warheads to proteins of interest. Get in touch with Vanitha Sekar if you want to meet us at the BIO-Europe’22 to learn more!
