The pore-forming protein perforin is a key component of the human immune response, performing a crucial role in the granule exocytosis pathway employed by natural killer (NK) cells and cytotoxic T lymphocytes (CTL) to eliminate virus-infected and transformed cells. CTLs and NK cells have also been implicated in several autoimmune diseases (e.g., insulin-dependent diabetes) and therapy-induced conditions (e.g., allograft rejection, graft-versus-host disease). Conventional immunosuppressive treatments indiscriminately depress immune function, but since perforin is expressed exclusively by cells of the immune system, inhibition of this target should be a highly selective strategy for the treatment of these conditions.
In this presentation I will report our initial identification of compounds that bind perforin protein using an NMR-based screen of small fragment molecules. I will then describe their optimisation to nanomolar inhibitors of human NK cells using structural and biological data. Finally, I will discuss the unexpected mode of action of these compounds and the implications of our findings for the design of future generations of perforin inhibitors.