Targeted protein degradation (TPD) is transforming drug discovery, providing a way to eliminate disease-causing proteins rather than simply blocking their activity. The European Laboratory Research & Innovation Group (ELRIG) 2025 meeting in Liverpool highlighted the latest innovations in this rapidly advancing field. Among the highlights was work from Ferran José’s lab at the Institute for Research in Biomedicine (IRB Barcelona), whose lab is exploring a novel approach: chemical rewiring of E3 ligases to expand the range of proteins that can be targeted for TPD.
E3 ligases help maintain balance in the cell by determining which proteins should be removed and when. They play a central role in the ubiquitin-proteasome system (UPS), where they label specific proteins with ubiquitin, marking them for destruction. Once tagged, these proteins are shuttled to the proteasome, where they are broken down into their basic components for recycling.
The human genome encodes more than 600 distinct E3 ligases, each with unique structural features and expression patterns. This diversity offers enormous potential for selective and tissue-specific therapeutics. However, most degrader molecules developed so far rely on just two of them — CRBN (cereblon) and VHL (von Hippel–Lindau) — largely because these are well-characterized and widely expressed. Although, a few others have recently been characterized.
Expanding this toolkit is crucial. By harnessing a broader range of E3 ligases, researchers could diversify degrader design, overcome challenges in E3 ligase resistance, and achieve greater precision in directing protein turnover in specific tissues or disease contexts. This is where Ferran José’s work comes in — using insights from viral biology to discover and repurpose new E3 ligases through what he describes as “chemical rewiring.”
Hijacking the cell’s degradation machinery
Evolution often finds smarter solutions than we can think of. By studying these special cases and converting them into something more general, we can design degraders in a very effective way.
- Ferran José, Institute for Research in Biomedicine
Viruses have evolved remarkable strategies to manipulate the host cell’s internal systems for their own survival. Successful viral replication often depends on the ability to co-opt cellular pathways, particularly those involved in protein degradation. To evade immune responses and promote their own replication, many viruses have learned to hijack host E3 ligases, redirecting them to degrade antiviral proteins or key regulators of the cell cycle.
“Imitating nature is a good idea,” Ferran explained to DDN. “Evolution often finds smarter solutions than we can think of. By studying these special cases and converting them into something more general, we can design degraders in a very effective way.”
By studying viral-host interactions, Ferran and his team aim to uncover E3 ligases that have already been proven hijackable by nature — suggesting that they can also be chemically reprogrammed to target disease-relevant proteins in human cells.
A computational hunt for new E3 ligases
To systematically identify E3 ligases that could be repurposed for targeted degradation, Ferran’s team began by mapping all known human E3 ligases — more than 600 in total. The goal was to find those that not only had available structural information but also showed evidence of viral interaction, indicating that they could be redirected through small molecules.
Using a custom computational pipeline developed in-house, the team scanned protein databases to compile and analyze E3-virus complexes. After applying all their criteria, five ligases met the requirements. Among these, one candidate stood out: FEM1C (Fem-1 Homolog C), a substrate receptor from the CRL2 (Cullin-RING Ligase 2) complex.
“FEM1C had a surface region that could be considered a pocket,” said Ferran. “That made it a good candidate for small-molecule binding. We wanted something selective enough to make a product that degrades the proteins we are interested in.”
Unlike many E3s, FEM1C’s structure contained a relatively open and accessible binding pocket — an encouraging sign for ligand design. But that openness also posed a challenge: mimicking or replacing the viral peptide, a large and complex molecule, with a much smaller drug-like compound would require precise chemical tailoring.
Finding a drug-like binder
Once FEM1C was identified, the next challenge was finding small molecules that could engage the ligase and act as a PROTAC. PROTACs, or proteolysis-targeting chimeras, are bifunctional molecules that simultaneously bind a protein of interest and an E3 ligase, bringing them together so the ligase can tag the target for degradation by the proteasome. This is a critical step as it provides the E3 connection needed to recruit and degrade disease-relevant proteins.
Using fluorescence polarization competition assays, the team screened candidate ligands and identified 14 promising binders. These molecules were evaluated not only for binding affinity but also for chemical novelty, avoiding functional groups associated with known E3 ligase binders or potential safety concerns. The most potent candidate from this set, C26, was then further optimized using a structure-driven approach, achieving the nanomolar-affinity lead compound C41.
Ferran explained the rationale: “Every E3 has a different structure, so we expected the small molecules to be structurally distinct. We are especially interested in PROTACs because they are easier to design — you just need a ligand for the E3 and a ligand for the target protein.”
Toward rational and scalable strategies
The broader vision, Ferran emphasized, is that systematic identification and chemical rewiring of novel E3 ligases could dramatically expand the degradable proteome. “Structural biology has already provided a lot of data, which helped us start and complete this project. In the future, more structures will allow us to explore additional ligases and targets.”
Ferran’s strategy complements other recent efforts in TPD, such as a study on DCAF2 (DDB1‐Cullin‐4‐associated factor‐2) from Frontier Medicines, which established a new E3 ligase through structural characterization and covalent engagement. While DCAF2 represents a single, experimentally characterized E3 platform, FEM1C illustrates how computational modeling and viral-inspired design can systematically uncover new ligases for drug discovery.
Together, these approaches highlight a shift in TPD — from reliance on a few ligases and serendipitous discovery to rational, scalable, and generalizable strategies.
