Group Leader: Philip Hogg

Overview:

A protein often contains strong bonds between pairs of cysteine amino acids in the polypeptide chain. These links are called disulphide-bonds because they join the sulphur atoms of the cysteine residues. The prevailing view is that disulphide-bonds have been added during evolution of the proteins to help hold them together, but that they are otherwise inert. My team’s research has shown that this is not necessarily the case. We have demonstrated that some disulphide-bonds can break or form in a way that has major consequences for how proteins work.

The implications for human biology are apparent when one considers that human cells make about 3,000 different proteins that contain disulphide-bonds. Furthermore, a major proportion of the proteins made by viruses, bacteria and plants also contain disulphide-bonds. No longer can these bonds only be thought of as structural motifs, but rather as potential switches that can control how a protein and therefore a tissue or organ works.

Our research focus is to characterise control of important proteins by disulphide switching, be able to predict disulphide switching in proteins, and to exploit disulphide switching for drug development.

We have shown that disulphide switching can control the activity of three proteins (plasmin, von Willebrand factor and CD4) and have preliminary data that supports control of another three proteins (tissue factor, CD8 and the prion protein) by this means. All six proteins play important roles in fundamental mammalian biology or pathobiology, including angiogenesis (new blood vessel formation), thrombosis (blood clotting), immunology and fatal neurodegenerative conditions.

As we learn more about how disulphide switching controls protein function the hope is that this knowledge can be used to predict whether a protein is likely to be controlled by this means based on its primary, secondary or tertiary structure. To this end, we have identified a type of disulfide-bond called a cross-strand bond that may be the first example of a generic disulphide switch.

Group Members:

Key Publications:

Lay, A.J., Jiang, X.-M., Kisker, O., Flynn, E., Underwood, A., Condron, R. and Hogg, P.J.
(2000) Phosphoglycerate kinase acts in tumor angiogenesis as a disulfide reductase. Nature 408, 869-873.

Xie, L., Chesterman, C.N. and Hogg, P.J. (2001)
Control of von Willebrand factor multimer size by thrombospondin-1. J. Exp. Med. 193, 1341-1349.

Matthias, L.J., Yam, P.T.W., Jiang, X.-M., Vandegraaff, N., Li, P., Poumbourios, P., Donoghue, N., and Hogg, P.J. (2002)
Disulfide exchange in domain 2 of CD4 is required for entry of the Human Immunodeficiency Virus Type 1. Nature Immunol. 3, 727-732.

Hogg, P.J. (2003) Disulphide-bonds as switches for protein function. Trends Biochem. Sci. 28, 210-214.

Don, A.S., Kisker, O., Dilda, P., Donoghue, N., Zhao, X., Decollogne, S., Creighton, B., Flynn, E., Folkman, J. and Hogg, P.J. (2003) A peptide trivalent arsenical inhibits tumor angiogenesis by perturbing mitochondrial function in angiogenic endothelial cells. Cancer Cell 3, 497-509.

Funding sources:

NH&MRC, ARC, NSW Cancer Council NSW, Australian Cancer Research Foundation, National Heart Foundation, Clive and Vera Ramaciotti Foundations

Commercial Activities:

We have developed a novel anti-cancer drug that is currently in formulation testing prior to a Phase I/IIa clinical trial in cancer patients which is scheduled to begin mid-2005. A new biotechnology company, Cystemix Pty. Ltd., has been incorporated to manage the scientific and commercial development of this drug. The drug and its analogues are protected by three international patents. The core patent has been accepted in Australia and is pending in Canada, Europe, Japan, USA and South Africa. The other two patents are pending in Australia, Canada, Europe, Japan, USA and South Africa.

We have also developed a novel imaging agent that can non-invasively detect dying and dead tumour cells in rodents. The agent also has the potential to image cell death in infracted heart muscle and brain. The ability to non-invasively measure dying and dead cells in tumours or damaged heart muscle or brain is an unmet need. For example, the agent could be used to assess the efficacy of a chemotherapy regimen by measuring within a few hours the extent of tumour cell death triggered by the drugs. The development of the imaging agent through a Phase I clinical trial in cancer patients in 2006 has now begun. A new biotechnology company will be formed by mid-2005 to manage the scientific and commercial development of this imaging agent. The technology is protected by an international patent that is pending in Australia, Canada, Europe, Japan, USA and South Africa.

Patents:

Inventors & Stage: Philip Hogg and Neil Donoghue; National Phase (PCT/AU00/01143, WO01/21628); Accepted in Australia (778781); Pending in Canada (2385322), Europe (2385322), Japan (2001-525003), USA (10/088540) and South Africa (03100944.4)
Description: A substantially cell membrane impermeable compound and use thereof

Inventors & Stage: Philip Hogg; National Phase (PCT/AU02/00310, WO2002/074305); Pending in Europe (EP02704485.8) and USA (09/744593)
Description: Use of a substantially cell membrane impermeable compound to treat arthritis

Inventors & Stage: Philip Hogg; National Phase (PCT/AU02/01523, WO2003/039564); Pending in Australia (2002340631), Canada (2466303), Europe (EP02774165.1), Japan (2003-541855), USA (09/744593) and South Africa (2004/3803)
Description: Selective targeting of apoptotic cells

Inventors & Stage: Philip Hogg; PCT (PCT/AU03/01483, WO2004/042079); Filed in Australia, Canada, Europe, Japan, USA and South Africa
Description: Induction of the mitochondrial permeability transition

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