Renal diseases are an important cause of cardiovascular and metabolic disease. More recently, molecular omics have provided the possibility to move from histology-based classification of disease to understanding of disease by mechanistic insights, thereby providing a powerful angle to drug discovery in renal diseases. We have contributed to this development in a team effort by discovering metabolic targets involved in renal and cardiovascular protection, the novel role of Nephrin-autoantibodies in minimal change disease, the characterization of human organoid models, and a long-standing track record to develop mass spectrometry-based omics approaches to map human and mouse glomerular and tubular tissue in disease. However, despite the knowledge of protein expression and modification, challenges exist to target distinct cells such as distal tubules or podocytes, to understand the function of kidney-specific transporters and the possibility to interfere with or degrade detrimental protein specifically.

In this project, we propose to leverage cutting-edge chemistry and advanced chemical proteomics to conduct - for the first time to the best of our knowledge - inverse drug discovery focused on relevant drug targets in the tubule and podocytes of the kidney. We will employ a collection of fragment-sized molecules to perform comprehensive mapping of their targets within the kidney tubule and glomerular proteome, which, methodologically, will involve both protein- and cysteine-directed activity-based protein profiling (ABPP). Analyses of the resulting target landscape (with single amino acid resolution) combined with structural biology, deep knowledge in kidney physiology and pathology, as well as kidney-specific large-scale screening assays to interrogate molecular and structural function, provides maximum opportunities to identify novel, ligandable kidney target (sites) of immediate relevance for cardiorenalmetabolic disease.