Abstract
The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, however inappropriate activity has also been implicated in certain auto-immune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro. Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection.
Highlights
Perforin is a 67 kDa, calcium-dependent glycoprotein expressed by only the natural killer (NK) cells and cytotoxic T lymphocytes (CTLs) of the mammalian immune system [1,2]
Perforin is synthesized and secreted into the immune synapse as a monomer, it rapidly binds to the target cell membrane through its calcium-dependent C2 domain [6,7] and oligomerises into large transmembrane pores composed of approximately 24 perforin monomers
Between our previous report [32] and the current study, we have explored in detail how changes made on a benzenesulphonamide-based template affects perforin inhibitory activity
Summary
Abstract The structure-activity relationships for a series of arylsulphonamide-based inhibitors of the pore-forming protein perforin have been explored. Perforin is a key component of the human immune response, inappropriate activity has been implicated in certain autoimmune and therapy-induced conditions such as allograft rejection and graft versus host disease. Since perforin is expressed exclusively by cells of the immune system, inhibition of this protein would be a highly selective strategy for the immunosuppressive treatment of these disorders. Compounds from this series were demonstrated to be potent inhibitors of the lytic action of both isolated recombinant perforin and perforin secreted by natural killer cells in vitro. Several potent and soluble examples were assessed for in vivo pharmacokinetic properties and found to be suitable for progression to an in vivo model of transplant rejection
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