Uromodulin is a protein that is produced by some kidney cells and is normally present in the urine. Molecules of uromodulin form filaments that can assemble into soluble molecular nets, capture bacteria and facilitate their elimination.
In patients with multiple myeloma, the cancer cells sometimes produce an excess of monoclonal light chains that are filtered into the urine. This can result in the elimination of large quantities of light chains into the urine. In some patients, the light chains interact with uromodulin, and form aggregates that obstruct renal tubules and lead to the development of acute kidney injury. These aggregates are called myeloma casts.
Extensive work performed in Dr Paul Sanders’ lab (University of Alabama, Birmingham) has deciphered the interactions between light chains and uromodulin, and shown that cast-forming light chains bind to a well-defined region of uromodulin via their complementarity-determining region 3 (CDR3). Dr Sanders has also shown that inhibiting the interactions between light chains and uromodulin can be highly effective in an in vivo model of cast nephropathy (J Clin Invest 2012;122:1777).
Using a natural product approach, Thrasos has developed small peptides that are derived from nephrotoxic light chains, interact with uromodulin and prevent its binding to light chains.
The lead compound, THR-8590, is a 13-amino acid cyclic peptide that competes with a series cast-forming light chains for the binding to uromodulin, and is highly stable and soluble.