(i) Inhibitors of Purple Acid Phosphatase
The enzyme purple acid phosphatase (PAP) is a binuclear metallohydrolase. This means that it contains two metal ions, in close proximity, in its active site. In human PAP these metals are Fe(II) and Fe(III). The purple colour typical of these enzyme arises from ligation of a tyrosine residue to the Fe(III) metal. The enzyme catalyses the hydrolysis of a range of phosphate esters.
The exact biological role(s) of the enzyme is not fully understood As well as our academic interest in this structurally unusual enzyme, we believe that PAP plays a crucial role in the disease osteoporosis. Osteoporosis arises from excessive bone resorption and leads to thinning of the bones and an increased risk of bone fracture.
Elevated levels of PAP are observed in patients with osteoporosis. Additionally, mice that over-express PAP develop osteoporosis. (Mice lacking the gene that expresses PAP present with the opposite morphology - osteopetrosis).
For these reasons we believe that inhibitors effective against PAP may lead to new treatments for osteoporosis. To this end we have designed, synthesised and assayed a number of these inhibitors, and we have successfully identified the most potent PAP inhibitor yet reported.
Molecular modelling of the docking of a small molecule inhibitor into human PAP (McGeary et al., Bioorg. Med. Chem. Lett., 2009, 19, 163-166).
This is a collaborative project within our School, with Associate Professor Gary Schenk (enzyme kinetics and mechanisms), Associate Professor Luke Guddat (protein X-ray crystallography) and Professor Lawrie Gahan (Model compounds and enzyme mechanisms).
Jeff Mak (Honours 2007) and Peter Vella (Honours 2008) made good progress on this project. Peter is continuing this work as part of his PhD studies, as is Annie Kan (Honours 2006). Projects suitable for Honours and PhD students are offered in this area.
(ii) Inhibitors of Metallo-beta-Lactamases
One of the great triumphs of modern medicine has been the introduction of the beta-lactam antibiotics to treat bacterial infections. Unfortunately, resistance to antibiotics occurs when bacteria evolve strategies to detoxify these antibiotics. The most common way they do this is to hydrolyse the lactam bond in these molecules using lactamases, thus deactivating them. Beta-lactam antibiotics are now frequently co-administered with lactamase inhibitors, but one class of lactamase, the metallo-beta-lactamases are problematic. No clinically effective inhibitors of metallo-beta-lactamases exist.
Like the PAP enzymes (see above) the metallo-beta-lactamases are binuclear metalloenzymes. In a collaborative project with Associate Professor Gary Schenk and Professor David Ollis at ANU, we are using a combination of characterisation of the enzyme, directed evolution and inhibitor design to identify lead compounds as enzyme inhibitors.
Peter Vella (Honours 2008) is working in this area as part of his PhD studies. Projects suitable for Honours and PhD students are offered in this area.
(iii) Fibroblast Growth Factor - Suramin Analogs
Suramin is an intriguing polysulfonated molecule that has been used for many years to treat serious tropical diseases such as African river blindness and African sleeping sickness. It has also been trialled for the treatment of a number of other diseases, including cancer and HIV.