School of Medical Sciences


Medicinal Chemistry - inhibitors of perforin as therapeutic immunosuppressive agents

Group leader


Current research


Inhibition of the Pore-Forming Protein Perforin

Pore-forming toxins (PFTs) are proteins with the ability to assemble into barrel-shaped pores which insert into cellular membranes. This process allows the delivery of toxic components through the pore to specific sites and/or leakage of cellular contents, leading to cell death.

PFTs are involved in invasion and infection by bacteria such as Staphlococcus aureus, Streptococcus pneumoniae and Anthrax. Eukaryotes also employ PFTs but for different reasons; either for attacking prey (for example as a venom constituent), or as a component of the immune system. It is the role of the PFTs in the function (or dysfunction) of the immune system which we aim to exploit in order to develop new immunosuppressive agents.

figure1

Figure 1: Crystal structure of a bacterial protein from P. luminescens which forms pores in a similar manner to perforin. Rosada et al, Science, 2007, 317, 1548-1551. 

Within the immune system, the key cytotoxic effector cells, cytotoxic T lymphocytes (CTL) and natural killer (NK) cells, provide a potent defence against viral infection and intracellular pathogens. Granule exocytosis is the major pathway used by cytotoxic lymphocytes to induce cell death and therefore eliminate virus-infected or transformed cells. Two of the main components found in the cytotoxic granules are a group of serine proteases (known as granzymes) and the PFT perforin, a calcium-dependent glycoprotein. Perforin undergoes cleavage of a short peptide sequence and then lipid and calcium binding, resulting in the assembly of highly ordered aggregates of 12-18 molecules that form trans-membrane pores. Like other PFTs, perforin utilises this mechanism to permeabilise cell membranes, allowing leakage of cell contents and, probably more importantly, entry of the granzymes which promote cell death. The presence of perforin in CTL and NK cells is essential for this process.

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Figure 2: The role of perforin in the granule exocytosis pathway.

These cells, howeverThese cells, however, have also been implicated in autoimmune disorders such as insulin-dependent diabetes, graft rejection and graft-versus-host disease. Thus the aim of the current project is to identify potent inhibitors of perforin as potential therapeutic immunosuppressive drugs. Currently accepted immunosuppression therapies have a wide range of side-effects, with multiple molecular targets being affected simultaneously. An inhibitor of perforin has the potential to specifically target the granule exocytosis pathway employed by CTLs and NK cells, thereby resulting in a potent immunosuppressive therapy with greatly reduced side-effects.

This programme is being conducted in collaboration with Professor Joe Trapani’s group at the Peter MacCallum Cancer Institute and Professor James Whisstock at Monash University.

Professor Joe Trapani

Professor James Whisstock

Other research interests


Medicinal chemistry related to the development of small-molecule inhibitors of the MAPK pathway for the treatment of cancer. Medicinal chemistry related to the development of new antibacterial agents.

Recent Publications


Lena, G., Trapani, J.A., Sutton, V.R., Ciccone, A., Browne, K.A., Smyth, M.J., Denny, W.A., Spicer, J.A. Dihydrofuro[3,4-c]pyridinones as inhibitors of the cytolytic effects of the pore-forming protein perforin. J. Med. Chem. 2008, 51, 7614-7624. 

Spicer, J.A. New small-molecule inhibitors of mitogen-activated protein kinase kinase. Expert Opin. Drug Discov. 2008, 3, 801-817.

Spicer, J.A., Rewcastle, G.W., Kaufman, M.D., Black, S.L. et al. 4-Anilino-5-carboxamido-2-pyridone derivatives as non-competitive inhibitors of mitogen-activated protein kinase kinase. J. Med. Chem. 2007, 50, 5090-5102.

Group members