Dist Prof Margaret Brimble

Organic Synthesis Team Leader

Professor Margaret Brimble’s research focuses on the synthesis of bioactive natural products and the synthesis of peptides, glycopeptides, and peptide mimetics as potential therapeutic agents. She developed the drug candidate NNZ2566 for Neuren Pharmaceuticals that is in phase 2b clinical trials for traumatic brain injury and Rett Syndrome. Her laboratory has also recently been licensed by Medsafe NZ to manufacture clinical grade peptides for the human clinical trials of melanoma vaccines. Margaret has been conferred with two Queen’s honours (MNZM 2004 and CNZM 2012) for her services to science.
In Biocide ToolBox, Margaret will be leading the organic synthesis team to synthesise the potential biocide candidates.

Background

Natural products have long been regarded as ‘nature’s medicine chest’ providing a rich source of lead compounds as invaluable platforms for developing front-line drugs. Our research focuses on making and modifying naturally occurring bioactive compounds that have been isolated from plants, animal tissue, microbes or marine and soil organisms, which are rare or hard to isolate in abundance. These compounds provide rich and diverse chemical structures that challenge the synthetic chemist to develop new flexible synthetic methodology for their construction. The preparation of synthetic analogues of the natural compound may improve the biological activity and provide an understanding of the mechanism of action of the naturally occurring compound.

Our research group also comprises a national peptide, peptidomimetic and glycopeptide chemistry facility that occupies a world-class laboratory in the Institute for Innovation in Biotechnology. The peptide synthesis laboratory supports growth in the burgeoning area of peptide therapeutics that is growing at twice the rate of small molecule therapeutics by engaging with the local biotech community to develop viable drug candidates based on peptide leads. An example is the development of NNZ2566 for Neuren Pharmaceuticals that is currently in phase 2b clinical trials for traumatic brain injury and was successful in phase 2 clinical trials for Rett Syndrome and has been given the name trofinetide by the WHO. Our laboratory has also been licensed by medsafe for the GMP manufacture of peptides for the clinical trial of melanoma vaccines (MELVAC trial).  The synthesis of natural product peptides containing unnatural amino acids, depsipeptides, cyclic peptides and natural proteins that exhibit potent antimicrobial activity, is one theme in our peptide chemistry laboratory. Analogues of the natural peptides are then synthesised to either simplify or stabilise the molecule with the aim of producing a more potent analogue. The ability to combine contemporary organic reactions such as cross-metathesis, “peptide stapling”, click chemistry, thiol-ene chemistry and the preparation of unnatural amino-acid building blocks with modern solid phase synthesis methods provides a powerful peptidomimetic platform to combat the problem of increasing resistance to existing antibiotics.  The peptide chemistry group also synthesizes peptide-based hydrogels with applications in bionanotechnology and regenerative medicine.

 

Current projects

  • Synthesis and Medicinal Chemistry of Natural Product Shellfish Toxins: New Pharmacological Probes for Treatment of Cardiovascular and Neurodegenerative Diseases and Anticancer Agents (with Dr Dan Furkert)

  • Drug Discovery Inspired by Traditional Chinese Medicines (TCM): Synthesis of Complex Bioactive Compounds as Treatments for Diabetes (with Dr Dan Furkert)

  • Asymmetric Synthesis of Benzannulated Spiroketals: Towards Novel Telomerase Inhibitors Based on the Rubromycin Family of Antibotics (with Dr Dan Furkert)

  • Total Synthesis and Structural Elucidation of the Anticancer Agent Callyspongiolide (with Dr Dan Furkert)

  • Synthesis of Pyrrole-containing Natural Products as Antibacterial Agents and Anti TB Agents (with Prof Greg Cook, University of Otago and Maurice Wilkins Centre for Molecular Biodiscovery)

  • Synthesis of the Anti-TB Agents the Peniphenones (with Dr Dan Furkert)

  • Medicinal Chemistry of Stable Analogues of Isochorismate: Antibiotics for Control of  Mycobacterium tuberculosis (TB) (with Dr Dan Furkert and Assoc. Prof Shaun Lott, Maurice Wilkins Centre for Molecular Biodiscovery)

  • Synthesis of Pyranonaphthoquinone Antibiotics as Anticancer Agents and Agents to Treat Viral Diseases

  • Understanding the Molecular Basis of Cannabinoid CB1 Receptor Ligand Binding for Modulation of CNS Cell Signalling Pathways (with Dr Dan Furkert and Assoc. Prof. Michelle Glass, Pharmacology, FMHS)

  • Towards Effective Antibody-Directed Cytotoxins (ADCs): Probing The Influence of Unnatural Amino Acid Components of Culicinin D, a Marine Natural Product (with Assoc. Prof. Adam Patterson and Dr Jeff Smaill, Maurice Wilkins Centre for Molecular Biodiscovery)

  • Synthesis of New Generation Lipopeptide-based Antibiotics Using Patented CLiPA Technology (with Dr Paul Harris, School of Biological Sciences)

  • Synthesis and Development of Antimicrobial Peptides Based on Teixobactin in the Fight Against Bacterial Resistance (with Dr Andrew Wadsworth, School of Biological Sciences)

  • Use of CH Activation for the Efficient Synthesis of Novel Cross-linked Amino Acids in the Novel Macrocyclic Peptide, Streptide – A Quorum Sensing Signaling Agent (with Dr Dan Furkert and Dr Paul Harris, School of Biological Sciences)

  • Synthesis of the Antimicrobial Bacteriocin Peptide Glycocin F and Analogues Thereof (with Assoc. Prof. Gillian Norris, Massey University)

  • Synthesis of Amylin Mimics (Pramlitide) as a Treatment for Diabetes (with A/Prof Debbie Hay, School of Biological Sciences)

  • Synthesis of Peptide Hormones and Natural Products (e.g. the Dianthins) for the Treatment of Diabetes and Osteoporosis (with Prof Jill Cornish, Auckland Bone Biology Group)

  • Synthesis of Advanced Glycation Endproduct (AGE Peptides) as Agents to Study Metabolic Disorders and Diabetic Heart Failure (with Dr. Kim Mellor, Department of Physiology and Prof Lea Delbridge, Department of Physiology, University of Melbourne)

  • Synthesis of GlycoPeptides and Lipopeptides as Novel Adjuvants for Cancer Vaccines (with Prof. Rod Dunbar, Maurice Wilkins Centre for Molecular Biodiscovery)

  • Synthesis of Functionalized Self-Assembling Peptides as Hydrogels for Regenerative Medicine  (with Prof Jill Cornish, Auckland Bone Biology Group)

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