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Special Technical Feature
Translational Research: the Next Generation of Therapeutics
Guest Editorial
Medical research in Australia has a proud record of delivering not only new mechanistic insights and discoveries
across a wide range of disciplines but also a number of valuable therapeutics. Notable examples are granulocyte
colony stimulating factor, the influenza neuraminidase inhibitor Relenza®, and the cervical cancer vaccine, to name
just a few. Indeed, potential applications to human medicine of our favourite molecules, either as new therapeutic
leads or targets for the development of new therapeutics, underpin much of our medical research (and certainly
achieve considerable prominence in grant applications to both the NHMRC and ARC). There are of course many
ways in which the fruits of our research can be translated into new therapeutics or improved medical practice; this
Special Technical Feature focusses on some of the methods that are at the cutting edge of drug development and that
promise to generate new therapeutic leads in the near future.
Structure-based drug design is a well-established approach in Australia, with Relenza® being a shining example
of its success. The knowhow that was nurtured at CSIRO to generate Relenza® now resides in the Structural Biology
and Chemical Biology Divisions at the Walter and Eliza Hall Institute (WEHI). In the first article Peter Czabotar,
Guillaume Lessene and Michael Roy from WEHI show how a combination of traditional medicinal chemistry and
structure-guided design can be used to drive the optimisation of hits identified by high-throughput screening (HTS),
with the goal of producing anti-cancer drugs targeting the Bcl-2 family of proteins.
An alternative approach to HTS for the generation of leads for medicinal chemistry optimisation is fragment-based
drug discovery or FBDD. Martin Scanlon and I describe the basis of this strategy and illustrate this approach with
some of the work being undertaken at the Monash Institute of Pharmaceutical Sciences. Compared with HTS, FBDD
offers a simpler and (importantly) cheaper entre into the generation of new leads, but a judicious combination of
medicinal chemistry and structure-guided design is still required for the efficient optimisation of hits.
An especially exciting advance in the field in recent years has been the development of peptides as therapeutics, and
it is encouraging to see the increased recognition of peptides as viable drugs by the pharmaceutical industry. Glenn
King provides a glimpse into the world of venom peptides, which constitute a bountiful but still largely unexplored
source of potential therapeutics and are already highly valuable pharmacological probes as a consequence of their
often exquisite potency and target selectivity. Glenn discusses recent progress in the discovery, characterisation and
delivery of venom-peptide therapeutics, and highlights venom peptides that might become first-in-class drugs for
treatment of autoimmune diseases and chronic pain.
Whatever their origin, and despite their attractions, peptides do present challenges as potential therapeutics. Their
synthesis or recombinant expression and purification can be expensive and oxidative folding is required if, as is often
the case, they contain multiple disulfide bridges. Moreover, most peptides are not orally bioavailable and stability in
biological fluids is often limited. Nonetheless, strategies to overcome these challenges are being developed, including
the replacement of disulfide bonds with carbon-carbon or diselenide bridges, backbone cyclisation and conjugation
to specific carriers.
This collection of articles provides just a snapshot of some of the excellent work being undertaken in Australia to
convert the fruits of our research into therapeutic leads and eventually new drugs. We hope that they will stimulate
you to consider applying one or more of these approaches to your favourite targets.
Ray Norton
Monash Institute of Pharmaceutical Sciences, Parkville, VIC 3052
Design of Therapeutics
Guest Editor: Ray Norton
[email protected]
In the ne xt issue...
5 Drug Discovery Against the Bcl-2 Family of Proteins: Controlling the Balance of
Life and Death
Michael Roy, Guillaume Lessene and Peter Czabotar
9 Fragment-based Drug Discovery, an Accessible Approach to New Therapeutics
Martin Scanlon and Raymond Norton
13 Venoms to Drugs: Translating Venom Peptides into Therapeutics
Glenn King
In April, the Showcase
on Research will be on
Chromatin and
Transcriptional
Regulation
Guest Editor:
David Tremethick
Cover Illustration
Structure of the pro-survival Bcl-2 family protein Bcl-xL (yellow) in complex with WEHI-539 (purple), a selective
inhibitor that induces apoptosis in cell lines dependent on Bcl-xL for survival. See the first article in this Special
Technical Feature for details. Image courtesy of Rachel Bucknall, Charles Reilly, Peter Czabotar and Guillaume Lessene.
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AUSTRALIAN BIOCHEMIST
Vol 44 No 3 December 2013