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.
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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.
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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.
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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
