Faces of CO-ADD: interview with Matthew Piggott
Associate Professor Matthew Piggott completed his BSc and PhD at The University of Western Australia. After postdoctoral stints at The Australian National University and Boston College, he took up a lecturing position at the ANU in the Department of Chemistry. In 2005 Matthew moved to the School of Chemistry and Biochemistry at UWA.
Matthew was The Judges and People’s Choice Winner for the CO-ADD Chemistry Prize competition ran earlier this year. Matthew and his colleagues have submitted 2500 compounds to the CO-ADD open access screening programme.
Photos from the Chemistry Lab of Dr Gavin Flematti, a natural products chemist at The University of Western Australia, showing part of the substantial compound collection in the background. (Left to right: Gavin Flematti, Abe Stevens, Matt Piggott). Thank you for your help in joining the CO-ADD initiative and sending us UWA's compound collection!
Abe Stevens hard at work packaging samples to send to CO-ADD. (Photos by Bob Bucat)
Faces of CO-ADD interview with Matthew Piggott
1. What is your research about?
Synthetic Organic Chemistry, Medicinal Chemistry and Chemical Biology
I love designing and synthesising new compounds. Sometimes this is done with a practical application in mind; for example, with the aim of discovering new drugs (medicinal chemistry), to study complex biological systems (chemical biology), or as molecular components of electronic circuits or machines. Sometimes, strategy and methodology are the focus: how can we make a complex, biologically active natural product as efficiently as possible? And, sometimes, the driving force is about pushing the boundaries. We can design molecules with unprecedented, beautiful structures – can we make them? In all cases, the creativity and logic of organic synthesis is immensely intellectually rewarding. Very brief overviews of current research areas are outlined below.
Parkinson’s disease medicinal chemistry: We have several projects investigating novel approaches to the pharmacotherapy of Parkinson’s disease, facilitated through a long-standing collaboration with Parkinson’s disease expert Dr Jonathan Brotchie, from the University Health Network, Toronto, Canada. The lead compound for one of these projects was the illicit drug MDMA (‘ecstasy’).
Trypanosomiasis medicinal chemistry: Trypanosomiasis includes African sleeping sickness and Chagas disease, major neglected diseases of the third world. This work involves a multipronged international collaboration with Professor Jonathan Baell at the Monash Institute of Pharmaceutical sciences, Melbourne; Professor Vicky Avery at the Eskitis Institute, Griffith University, Brisbane; and GlaxoSmithKline, through the Tres Cantos Open Lab Foundation.
Chemical Biology: Efforts in this area include the synthesis of stable analogues of phosphohistidine for the purpose of antibody generation, and histidine phosphatase/kinase inhibitor identification, in collaboration with Professor Paul Attwood from UWA; the design and synthesis of fluorescent probes of enzyme activity; and biological probes for the interrogation of protein oxidation state with Professor Peter Arthur from UWA.
Total synthesis of natural products: Our group has achieved the novel total synthesis of 11 biologically-active natural products. Additional synthetic work has refuted several structures assigned to natural products.
Design and synthesis of compounds with novel aromatic architectures: Through collaboration with UWA Professors George Koutsantonis and Paul Low, we are currently investigating the synthesis of novel organometallic complexes with potential applications as molecular switches.
2. What sort of compounds are you screening for antimicrobial activity with CO-ADD?
The majority of compounds we are sending to CO-ADD are historical samples, collected over many decades, from research projects in the Department to Chemistry at UWA. These projects have primarily involved natural products isolation and structural elucidation, and total synthesis of natural products. Current research group leaders are also submitting their compound collections, arising from projects in medicinal chemistry, chemical biology, total synthesis, bioactivity-guided natural product chemistry, method development and catalysis, and materials chemistry.
3. How will CO-ADD contribute to your research?
As a medicinal chemist I always have my eye out for new ideas for drug discovery research projects, and screening hits for hit-to-lead optimisation. Finding reliable collaborators to assess the biological activity of compounds specifically synthesised for med-chem projects is a challenge, and I hope that this kind of interaction can continue with CO-ADD.
I’m particularly interested to see if some of the compounds we’ve discovered that have potent activity against trypanosomes (protozoan parasites that cause African sleeping sickness and Chagas disease), also have antibacterial and/or antifungal activity.
4. How can chemistry fight the war on superbugs and help find the next antibiotic?
Chemists and chemistry are central to our ongoing battle with the bugs. Without the chemists, you don’t have the small molecules to screen for antimicrobial activity, and small molecule drugs are still the best defense against microbial infections that overwhelm our immune systems. In addition, it’s unlikely that the screening hits that CO-ADD turn up will be ready for the clinic. Substantial medicinal chemistry (optimisation of potency, selectivity and pharmacokinetic properties) will likely be required. Given the lack of financial drivers for commercial antimicrobial discovery and development, academic groups will play an important role in this area.
5. What's next for you?
We eagerly await the results of screening of the UWA compound collection, and as alluded to above, I hope that the collaboration with CO-ADD evolves from random screening into logical antimicrobial drug discovery. We will also continue to send CO-ADD new compounds, made for other purposes, in the search for the next drug lead.
While antimicrobials are literally life-savers, it seems increasingly clear that decimating our natural microbiome to clear one pathogenic microbe may be detrimental to our long-term health. Historically, broad-spectrum antimicrobials have been most highly prized, but with improvements in diagnostic capabilities, perhaps we should be searching for more selective drugs that can take out the bad bugs with minimal collateral damage?