Molecular cut-and-sew process could speed up drug design

An innovative molecular ‘cut and sew’ process developed by scientists at the University of Dundee has enabled the design of a research tool that will accelerate the design of drugs for diseases for which no other options exist, especially cancer.

Experts at the University’s Center for Targeted Protein Degradation have created a new personalized version of a protein that is commonly hijacked by molecules known as “protein degraders”. The process removes unwanted pieces of the protein before the remaining parts are assembled, allowing researchers to isolate the protein and work with it more efficiently in the laboratory.

This pioneering work was published in the journal, Natural communications.

Protein degraders herald a revolution in drug discovery, with more than 50 such drugs currently being tested in clinical trials. These types of molecules work in a fundamentally different way than conventional drugs.

Instead of simply blocking disease-causing proteins, degrading drugs recruit or hijack them to stick to an important protein called ubiquitin E3 ligase, which is part of the cellular protein recycling machinery. This recruitment is fundamental for the functioning of the drug and leads to the destruction and complete elimination of the pathogenic protein from inside the cell.

The majority of drugs currently given to patients that work in this way hijack a single E3 ligase called Cereblon (CRBN). So far, approaches to designing safer, more drug-like molecules and understanding how they recruit disease-causing proteins to CRBN have been slow and ineffective.

However, the Dundee team, led by structural biologists Alena Kroupova and David Zollman, in Professor Alessio Ciulli’s group, devised an ingenious approach to engineering a new variant of the protein which they called ‘CRBN-midi’. . “

This involves removing unwanted bits from the protein and sewing the remaining parts together. This improves the ability to isolate the protein and work with it in the laboratory.

Dr Kroupova, first author of the study, said: “Our variant of the CRBN protein is more soluble and more easily crystallizable than the parent protein, while behaving closely with it and retaining its biological characteristics.

“This makes it ideally suited to many experiments and processes now widely used in the field of targeted protein degradation.

Dr. Zollman, co-corresponding author of the study, added: “As TPD revolutionizes the world of drug design, this advance will help accelerate the generation of new degradative drugs that act via this protein, which will benefit ultimately to patients living with some of the most pressing health challenges of our time.

“We have made our CRBN-midi reagent widely available to the scientific community, without restrictions or conditions, via the Addgene portal. It has already been very popular since we first released it as a preprint in January 2024,” said Professor Ciulli. .

“Many research groups around the world, including academia and the biopharmaceutical industry, are already using it for their research and drug discovery programs.”