Abstract:Dihydrofuro[3,4-c]pyridinones are the first class of small molecules reported to inhibit the cytolytic effects of the lymphocyte toxin perforin. A lead structure was identified from a high throughput screen, and a series of analogues were designed and prepared to explore structure-activity relationships around the core bicyclic thioxofuropyridinone and pendant furan ring. This resulted in the identification of a submicromolar inhibitor of the perforin-induced lysis of Jurkat T-lymphoma cells.
“…The one unexpected outlier was the 3-cyano compound 49 which, although it had poor activity against isolated recombinant perforin, had excellent activity against perforin produced by whole NK cells. The NK cells also retained excellent viability across all examples, consistent with our previous findings for this series [32] and in contrast to earlier reported classes [26], [27], [28].…”
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.
“…The one unexpected outlier was the 3-cyano compound 49 which, although it had poor activity against isolated recombinant perforin, had excellent activity against perforin produced by whole NK cells. The NK cells also retained excellent viability across all examples, consistent with our previous findings for this series [32] and in contrast to earlier reported classes [26], [27], [28].…”
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.
“…As perforin is directly implicated in b-cell damage, both directly and through facilitating the delivery of granzymes, it is potentially an important target for pharmacological inhibition. The first small molecule inhibitors of perforin were recently described, 82 and await evaluation in mouse models of type I diabetes and other perforindependent immunopathologies. Long-term generalized inhibition of perforin is unlikely to be a therapeutic option based on the clinical condition called familial hemophagocytic lymphohistiocytosis because of perforin deficiency.…”
Type 1 diabetes results from autoimmune destruction of pancreatic b-cells by CD8 þ T cells. The requirement for CD8 þ T cells implicates perforin and granzymes as effectors of tissue destruction. Diabetogenic cytotoxic T cells kill b-cells by the perforin/ granzyme pathway in vitro. In the non-obese diabetic mouse model of type I diabetes, perforin deficiency results in a highly significant reduction in disease, indicating a direct role for perforin in b-cell death in vivo, although other cell death pathways must account for the residual diabetes in perforin-deficient mice. Perforin and granzyme B are also important in allogeneic destruction of islets. The dominant role of the perforin/granzyme pathway in b-cell destruction in type I diabetes and allogeneic islet graft rejection make this pathway an important target for blockade in future therapies for type I diabetes. In addition, granzymes have a newly recognized role in inflammation, a feature of both type I and II diabetes, suggesting their role should be further explored in both the common forms of diabetes.
“…We also present evidence that, in the context of DC immunotherapy, this perforin-dependent checkpoint operates during a brief period soon after DC administration. Therefore, our results suggest that, paradoxically, a temporary blockade of T cell-mediated cytotoxic function at the time of DC vaccination, as would be rendered possible by the development of perforin inhibitors, 40 may maximize the efficacy of DC-based immunotherapy.…”
Dendritic cells (DCs) are powerful activators of primary and secondary immune responses and have promising activity as anticancer vaccines. However, various populations of immune cells, including natural killer cells, regulatory T cells and especially cytotoxic T lymphocytes (CTLs), can inhibit DC function through cytotoxic clearance. Spontaneous tumor-specific CTL responses are frequently observed in patients before immunotherapy, and it is unclear how such pre-existing responses may affect DC vaccines. We used an adoptive transfer model to show that DC vaccination fail to induce the expansion of pre-existing CTLs or increase their production of interferon γ (IFNγ). The expansion and effector differentiation of naïve host CD8+ T cells was also suppressed in the presence of CTLs of the same specificity. Suppression was caused by the cytotoxic functions of the adoptively transferred CTLs, as perforin-deficient CTLs could respond to DC vaccination by expanding and increasing IFNγ production. Proliferation and effector differentiation of host CD8+ T cells as well as resistance to tumor challenge were also significantly increased. Expression of perforin by antitumor CTLs was critical in regulating the survival of vaccine DCs, while FAS/FASL and TRAIL/DR5 had a significant, but comparatively smaller, effect. We conclude that perforin-expressing CTLs can suppress the activity of DC-based vaccines and prevent the expansion of naïve and memory CD8+ T cells as well as antitumor immune responses. We suggest that, paradoxically, temporarily blocking the cytotoxic functions of CTLs at the time of DC vaccination should result in improved vaccine efficiency and enhanced antitumor immunity.
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