Facilitating innovation - A robust and reliable platform for early-stage drug discovery and tool compound development

Our organisms are powered by biochemical reactions from molecular machines often made up of individual proteins or protein complexes. Proteins are responsible for tens of thousands if not millions of molecular interactions either with each other (protein-protein interactions) or with small molecule ligands, metabolites and drugs (protein-ligand interactions).

Measuring these interactions precisely and in high-throughput is a major challenge and forms the basis for our understanding of how biological molecular machines work and for imagining new ways to develop therapeutic drugs to treat diseases.

We would acquire a Dianthus instrument that can precisely and robustly measure protein-protein and protein-ligand interactions in solution where optimal conditions for protein stability can be maintained. The instrument can simultaneously use two detection modes based on two different biophysical techniques: a spectral shift technology and a temperature related intensity change (TRIC) technology.

Each has its own advantages, and the combination is really powerful in improving detection sensitivity (allowing us to use less of the precious materials we make) and can signpost potential "bad" reactions that need repeating or are untrustworthy.

Doing experiments in a high-throughput format with a 384-well plate measuring >1000 reactions per hour will significantly accelerate our ability to discover new molecules as tools to understand biology and disease conditions. It will transform the way we discover and optimise drug candidates for early-stage drug discovery programs. We use multiple screening platforms to identify drug candidates and have a combination of techniques and expertise to optimise "hit" compounds.

However, we lack a technology that can provide affinity measurements and rank our molecules according to their ability to bind or "stick" to our biological targets. The Dianthus instrument will bridge this crucial, informative gap in our discovery pipeline.

Many of our projects will benefit from this technology. New enzyme families and drug candidates in the ubiquitin proteasome system promise to benefit inflammatory diseases (e.g. Lupus, Sclerodema, Rheumatoid Arthritis) and multiple types of cancer.

These are hard targets because as large multimeric complexes they are difficult to produce and assay with current technology. Similarly, self-assembling systems that form protein fibrils and contribute to amyloidosis in Alzheimer's and type II diabetes are hard to study with current techniques. The new instrument will make it easier to discover molecules that prevent fibril formation.

We have teams working on challenging targets that control protein folding and energy flow in mitochondria with promising molecules that may benefit patients with an aggressive and hard-to-treat brain cancer (glioblastoma). We made huge progress with membrane proteins that are targets for malaria, antibiotic resistance and heart disease and are developing new ways to drug these proteins.

The 384-well plate system is also ideal for a ligand-discovery platform developed in Leeds which also performs chemical reactions in 384-well plates, ensuring perfect compatibility.

Finally, we are using Dianthus to understand fundamental biology by measuring interactions of protein complexes with DNA to study how DNA damage is repaired. This will further our knowledge of disease biology and help us unveil a cell's "Achilles hill" to unlock new therapeutic targets in cancer.

At time of writing, no UK institution has installed this technology. As such, the Dianthus instrument will be an amazing unique addition to our multiuser research facilities and complement our current capabilities. The instrument will also be hugely beneficial to the Leeds science ecosystem and local universities through our equipment sharing portal for northern universities and other interested institutions.