Sodium/hydrogen exchangers (NHEs) are ubiquitously present in all biological phylae. These integral membrane proteins are secondary active ion transporters that mediate the exchange of cations with protons across lipid bilayers. In mammals, NHEs are encoded by the SLC9 gene family and reside in the plasma membrane or in membranes of intracellular organelles (e.g. endosomes).

NHA2 (SLC9B2) is a recently discovered endosomal NHE expressed in a subset of specialized cells including osteoclasts, pancreatic β-cells and distal tubular cells of the kidney. In the first two phases of the NCCR we discovered that NHA2 plays an important role in renal blood pressure homeostasis and electrolyte handling and is critically involved in insulin secretion in the endocrine pancreas. By combining ligand based virtual screening and wet bench screening, we identified potent NHA2 inhibitors (IC50s in the low nanomolar range) and studied in detail the synthetic chemistry and SAR landscape of these novel compounds.

We are currently investigating NHA2 function at a cellular and molecular level and exploring the functional interaction of NHA2 with other NHEs in the endosome (NHE6 and NHE) to better understand the role of NHA2 health and disease. In addition, we are extending our screening efforts to other endosomal NHEs, including NHE6 and NHE9, with the goal to develop specific and highly potent pharmacological agents suitable for preclinical studies.

This multidisciplinary project involved the groups of Prof. Jean-Louis Reymond and Prof. Christoph von Ballmoos (both DCB, University of Bern) and Prof. Daniel Fuster (Inselspital, Bern University Hospital).