Benzenesulphonamide inhibitors of the cytolytic protein perforin

Spicer, Julie A.; Miller, Christian K.; O’Connor, P. D. T.; Jose, Jiney; Huttunen, Kristiina M.; Jaiswal, Jagdish K.; Akhlaghi, Hedieh; Browne, Kylie A.; Trapani, Joseph A.

doi:10.1016/j.bmcl.2016.12.057

Cited by 12 publications

(43 citation statements)

References 18 publications

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“…Finally, based on our results we aimed to test a therapeutic approach for fulminant hepatitis. We have recently developed a new class of small molecule perforin inhibitors based on benzenesulphonamide chemistry that are suitable for use in vivo 34 , 35 . The compounds potently inhibit human and murine perforin, but have no effect on TNF-mediated cell death in vitro (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

et al. 2018

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CD8 T cells protect the liver against viral infection, but can also cause severe liver damage that may even lead to organ failure. Given the lack of mechanistic insights and specific treatment options in patients with acute fulminant hepatitis, we develop a mouse model reflecting a severe acute virus-induced CD8 T cell-mediated hepatitis. Here we show that antigen-specific CD8 T cells induce liver damage in a perforin-dependent manner, yet liver failure is not caused by effector responses targeting virus-infected hepatocytes alone. Additionally, CD8 T cell mediated elimination of cross-presenting liver sinusoidal endothelial cells causes endothelial damage that leads to a dramatically impaired sinusoidal perfusion and indirectly to hepatocyte death. With the identification of perforin-mediated killing as a critical pathophysiologic mechanism of liver failure and the protective function of a new class of perforin inhibitor, our study opens new potential therapeutic angles for fulminant viral hepatitis.

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Section: Resultsmentioning

confidence: 99%

Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

et al. 2018

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“…The majority of the target compounds were constructed from right to left starting with our previously published key iodide 75 [32] ( Scheme 1 ). Suzuki reaction of 75 with a variety of commercially available aminopyridine boronates under standard conditions gave the required amine intermediates 76 – 79 which were subsequently reacted with a range of substituted aryl sulphonyl chlorides.…”

Section: Resultsmentioning

confidence: 99%

“…Suzuki reaction of 75 with a variety of commercially available aminopyridine boronates under standard conditions gave the required amine intermediates 76 – 79 which were subsequently reacted with a range of substituted aryl sulphonyl chlorides. The 5-amino-3-pyridine derivative 78 [32] in particular was employed in the preparation of all compounds in Table 3 . One exception was where the central pyridine ring was replaced with a benzene; in this case the Suzuki step was carried out with 2-methyl-5-nitrobenzeneboronic acid, the nitro compound ( 80 ) hydrogenated to give the amine ( 81 ), which was then reacted with either 2,4-difluorobenzenesulphonyl chloride or 2-pyridinesulphonyl chloride to afford 13 and 15 respectively.…”

Section: Resultsmentioning

confidence: 99%

“…This issue was only overcome when we amalgamated our own finding that an aryl sulphonamide could act as a bioisosteric replacement [30] with a strategy implemented by GSK workers, where a thiazolidinedione was replaced with a pyridyl-linked benzenesulphonamide to give 2 [31] . This approach resulted in a new series of benzenesulphonamide-based perforin inhibitors, exemplified by 3 , which were potent, soluble and essentially non-toxic toward NK cells [32] . In the following report we extend our study to explore whether it is possible to further modulate activity and physicochemical properties through variation of the sulphonamide linker, linker position, and substitution on the central pyridine ring and terminal benzene ( Fig.…”

Section: Introductionmentioning

confidence: 99%

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Substituted arylsulphonamides as inhibitors of perforin-mediated lysis

Spicer

Miller

O’Connor

et al. 2017

European Journal of Medicinal Chemistry

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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.

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“…Location in the cell Intracellular cytolytic granules (39) Membranes of intracellular endosomes (46,47) Function in GD T cells Lysis of transformed or infected cells (39)(40)(41) Destruction of intracellular bacteria (46,47) Stimulatory factors Surface receptors: -GD TCR 53 suffering from these illnesses. Compounds identified as Perforin inhibitors in NK and AB T cells include diarylthiophenes and benzenesulfonamide based therapeutics (83)(84)(85). In short, cutaneous GD T cells express Perforin upon activation and this activation can be achieved through a variety of mechanisms including stimulation of the TCR, ligation of costimulatory molecules, and cytokine stimulation ( Table 1).…”

Section: Perforinmentioning

confidence: 99%

Perforins Expression by Cutaneous Gamma Delta T Cells

et al. 2020

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Gamma delta (GD) T cells are an unconventional T cell type present in both the epidermis and the dermis of human skin. They are critical to regulating skin inflammation, wound healing, and anti-microbial defense. Similar to CD8+ cytotoxic T cells expressing an alpha beta (AB) TCR, GD T cells have cytolytic capabilities. They play an important role in elimination of cutaneous tumors and virally infected cells and have also been implicated in pathogenicity of several autoimmune diseases. T cell cytotoxicity is associated with the expression of the pore forming protein Perforin. Perforin is an innate immune protein containing a membrane attack complex perforin-like (MACPF) domain and functions by forming pores in the membranes of target cells, which allow granzymes and reactive oxygen species to enter the cells and destroy them. Perforin-2, encoded by the gene MPEG1, is a newly discovered member of this protein family that is critical for clearance of intracellular bacteria. Cutaneous GD T cells express both Perforin and Perforin-2, but many questions remain regarding the role that these proteins play in GD T cell mediated cytotoxicity against tumors and bacterial pathogens. Here, we review what is known about Perforin expression by skin GD T cells and the mechanisms that contribute to Perforin activation.

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Benzenesulphonamide inhibitors of the cytolytic protein perforin

Abstract: Graphical abstract

Cited by 12 publications

References 18 publications

Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

Perforin inhibition protects from lethal endothelial damage during fulminant viral hepatitis

Substituted arylsulphonamides as inhibitors of perforin-mediated lysis

Perforins Expression by Cutaneous Gamma Delta T Cells

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