Dr Chrisopher Squire

Senior Lecturer

Structural Biology

Phone: +64 9 3737599 ext 88806
Rm 110-403
Email: c.squire@auckland.ac.nz

Research Interests

Selected research topics include:

1. Poxvirus Entry-Fusion Complex

Poxviruses are large dsDNA viruses containing unique sets of genes transcribed early in the infection life cycle that modulate the host immune response. Our collaborator Dr. Andrew Mercer (Otago University) has characterized a number of these genes and their protein products unique to orf virus – a pox virus that infects sheep and humans and costs New Zealand millions of dollars in export earnings every year. We aim to characterize these proteins using X-ray crystallography, small angle X-ray scattering (SAXS), and other biophysical techniques, to better understand the biological processes underlying the course of poxvirus infection. Of particular interest is the poxvirus fusion process. Poxviruses fuse with their host cell using an entry-fusion complex consisting of 11 or more individual proteins. A recent structure prediction from our laboratory has suggested that poxviruses contain a conserved pilin-like protein involved in viral fusion. However, pilin proteins are normally only found in bacteria as part of their cell fusion machinery. The confirmation of this protein as a viral pilin via various biophysical techniques, would be a highly novel result and would help clarify the virus-host cell fusion process.

2. Enzymatic prodrug activation – a new paradigm in cancer drug discovery

Medical researchers in the Auckland Cancer Society Research Centre (ACRSC) have discovered a novel activation mechanism for a series of anticancer prodrugs (one of which has reached stage II clinical trials) involving enzymatic nitroreduction. Prodrugs are inactive forms of potentially toxic or unstable drug compounds that are activated selectively at tumour sites. We aim to characterize the structural basis of the enzymatic activation of a family of DNA-targeting nitrogen mustards via X-ray crystallography, thermal stability analysis, UV fl uorescence, and mutational and functional assays of the protein. Currently, we have one protein crystal structure containing a prototype mustard, the compound currently in stage II trials, with the aim of investigating others in the series. We aim to provide feedback to the chemists in the ACSRC so they can develop more selective and more powerful anticancer prodrugs. See http://www.fmhs.auckland.ac.nz/sms/acsrc/ttt/default.aspx

3. Fragment screening for drug discovery

Fragment screening is a widely-used, contemporary method used in drug discovery. Hundreds of small fragments of drug-like molecules are mixed with target protein and their binding assessed by thermal stability assays, NMR, molecular modelling, and X-ray crystallography. Fragments can then be “grown” to fit better the protein active site or two fragments can be linked chemically to make a larger drug-like molecule. Currently, we have drug targets from M. tuberculosis, human cancer targets, and immunology targets. These projects involve many other research groups from the School of Biological Sciences, Auckland Cancer Society Research Centre, and the Chemistry Department, with expertise in immunology, cancer biology, synthetic chemistry, and molecular modelling.

Recent Publications