Inhibition of the Cytolytic Protein Perforin Prevents Rejection of Transplanted Bone Marrow Stem Cells in Vivo

Perforin is a key
effector protein in the vertebrate immune system
and is secreted by cytotoxic T lymphocytes and natural killer cells
to help eliminate virus-infected and transformed target cells. The
ability to modulate perforin activity in vivo could be extremely useful,
especially in the context of bone marrow stem cell transplantation
where early rejection of immunologically mismatched grafts is driven
by the recipient’s natural killer cells, which overwhelmingly
use perforin to kill their targets. Bone marrow stem cell transplantation
is a potentially curative treatment for both malignant and nonmalignant
disorders, but when the body recognizes the graft as foreign, it is
rejected by this process, often with fatal consequences. Here we report
optimization of a previously identified series of benzenesulfonamide-based
perforin inhibitors for their physicochemical and pharmacokinetic
properties, resulting in the identification of 16, the
first reported small molecule able to prevent rejection of transplanted
bone marrow stem cells in vivo by blocking perforin function.