Biologically Active Cyclic Peptides
Biologically
Active Cyclic Peptides
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Tubulin-binding compounds such as the ustiloxins & phomopsins (red) inhibit polymerisation of tubulin dimers (green/blue) into microtubules. |
X-ray crystal structure of a tubulin dimer with bound drug. |
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Current efforts are being directed towards the synthesis of several complex cyclic peptides. The ustiloxins & phomopsins are a family of tubulin-binding cyclic peptides which have shown potent in vitro anti-tumour activity, particularly against human breast and lung cancer cell lines. The pneumocandins and microsclerodermins are antifungal cyclic peptides that contain several poly-hydroxylated amino acids, and are currently undergoing clinical trials for the treatment of HIV-related fungal infections. The general synthetic strategy involves developing methods for the stereocontrolled synthesis of the highly functionalised amino acid residues present in these peptides, followed by the development of procedures for the assembly of the amino acid components into the final cyclic peptides.
Inhibitors of Lysine Biosynthesis
Compounds which inhibit biosynthesis of the amino acid L-lysine represent a potential new class of antibiotics and herbicides, as lysine is required for biosynthesis of proteins and the bacterial cell wall. The first committed step in lysine biosynthesis is the conversion of pyruvate and aspartate semi-aldehyde (ASA) to dihydrodipicolinic acid (DHDP), a process catalysed by the enzyme DHDP synthase (DHDPS). Product analogues have been designed as potential inhibitors of DHDPS.
First committed
step in lysine biosynthesis – catalysed by DHDP synthase
Additionally, the mechanism of DHDPS has not been rigorously established, with recent reports suggesting that HTHDP is the true enzyme reaction product, which undergoes spontaneous dehydration in solution to give DHDPS. Studies are being conducted to gain more insight into the enzyme mechanism.
Cross-linked Tyrosine Derivatives in Peptides and Proteins
We are developing novel methods for the preparation of cross-linked tyrosine derivatives, such as dityrosine, trityrosine and pulcherosine. The formation of these tyrosine derivatives in proteins has been associated with a variety of diseases and disorders, including Alzheimer’s and Parkinson’s diseases. Non-specific formation of cross-linked tyrosine residues has been shown to be a biological marker of oxidative stress, and plays a critical role in the signalling of protein degradation and cellular damage.
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Craig Hutton
email: chutton@unimelb.edu.au