Distinguished Professor Margaret Anne Brimble
MSc (Auckland), PhD (Southampton, UK)
Research | Current
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.
- 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)
Find more information about Margaret's research on the Brimble Group website.
2015: IUPAC Distinguished Women in Chemistry/Chemical Engineeering Award; University of Auckland Vice-Chancellor’s Commercialization Medal; Senior Fellowship Award International Society of Heterocyclic Chemistry
2014: Westpac Trust Women of Influence Award (Science and Innovation)
2012: Queen’s Honour - Companion of the New Zealand Order of Merit for Service to Science; Appointed Distinguished Professor at The University of Auckland; RSNZ – Rutherford Medal (Exceptional Contributions to NZ Science & Technology); RSNZ – Hector Medal (Outstanding Contributions to Chemical Sciences); RSNZ – MacDiarmid Medal (Outstanding Scientific Research for Human Benefit)
2011: RACI (Aus) Adrien Albert Award - Medicinal Chemistry; Dean’s Award for Excellence in Postgraduate Supervision
2010: RSC (UK): Natural Products Chemistry Award; Simonsen Lectureship; Editorial Board Award
2008: World Class New Zealander Award (Research, Science, Technology & Academia), Kea and NZ Trade & Enterprise
2007: L'ORÉAL-UNESCO Women in Science Laureate Asia/Pacific
2004: Queen’s Honour - Member New Zealand Order of Merit Service to Science; RSNZ - James Cook Research Fellowship; Novartis Chemistry Award and Lectureship; Inaugural UK Royal Society Rosalind Franklin International Lectureship
Areas of expertise
Expertise: Inventor – Trofinitide (NNZ2566) – first drug for Rett Syndrome; in phase 2 clinical trials for Traumatic Brian Injury, Concussion, Fragile X Syndrome (Neuren Pharmaceuticals); Organic Synthesis; Medicinal Chemistry; Drug Development; Natural Products; Agrochemistry; GMP synthesis melanoma vaccines (phase 1 trial); Consultant/Expert Witness - pharmaceutical companies.
Interests: Synthesis of: bioactive natural products and traditional Chinese medicines; rhinovirus 3C protease inhibitors; telomerase inhibitors; antimicrobial peptides; cell penetrating peptides; peptidomimetics; alkaloids as neuroprotective agents; glycopeptides, lipopeptides, cGMP peptides as vaccine components; fish antifreeze peptides; agrochemicals. Organocatalysis. Synthesis of neo-glycopeptides, neo-phosphopeptides, neo-lipopeptides using click chemistry and olefin metathesis. Synthesis of small proteins, glycopolymers and hydrogels.
Distinguished Professor, Chair of Organic and Medicinal Chemistry, Director of Medicinal Chemistry, Chair of the Royal Society of New Zealand Rutherford Foundation, Vice-President of Organic and Biomolecular Division of the International Union of Pure and Applied Chemistry, Member of the European Research Council PE5 panel for Synthetic Chemistry and Materials Science, Member of International Society of Heterocyclic Chemistry, Principle Investigator and member of the management committee of Maurice Wilkins Centre for Molecular Biodiscovery, Principal Investigator in Brain Research NZ.
Selected publications and creative works (Research Outputs)
- Quach, R., Furkert, D. P., & Brimble, M. A. (2017). Gold catalysis: synthesis of spiro, bridged, and fused ketal natural products. Org Biomol Chem10.1039/c7ob00496f
Other University of Auckland co-authors: Daniel Furkert
- Medini, K., West, B., Williams, D. E., Brimble, M. A., & Gerrard, J. A. (2017). MALDI-imaging enables direct observation of kinetic and thermodynamic products of mixed peptide fiber assembly. Chem Commun (Camb), 53 (10), 1715-1718. 10.1039/c6cc10146a
Other University of Auckland co-authors: David Williams, Karima Medini
- Siow, A., Hung, K.-Y., Harris, P. W. R., & Brimble, M. A. (2017). Solid-Phase Synthesis of the Peptaibol Alamethicin U-22324 by Using a Double-Linker Strategy. European Journal of Organic Chemistry, 2017 (2), 350-354. 10.1002/ejoc.201601102
Other University of Auckland co-authors: Paul Harris
- Lutteroth, K. R. (2017). An Investigation into the Key Structural Role of Glycosylated Lysine Residues in the Collagenous Domain of Adiponectin, a Potential Therapeutic for Type II Diabetes The University of Auckland. ResearchSpace@Auckland.
- Jay-Smith, M. G. (2017). Exploring the Synthetic Development of New Rodenticides: Palatability and efficacy studies of the rat-selective toxicant norbormide; and the design and synthesis of novel carbon monoxide releasing molecules The University of Auckland. ResearchSpace@Auckland.
- Amso, Z. (2017). Synthetic Peptides as Potential Therapies for Osteoporosis and Bacterial Infections: Design, Synthesis, and Biological Evaluation The University of Auckland. ResearchSpace@Auckland.
Other University of Auckland co-authors: Zaid Amso
- Naysmith, B. J., Hume, P. A., Sperry, J., & Brimble, M. A. (2017). Pyranonaphthoquinones – isolation, biology and synthesis: an update. Nat. Prod. Rep10.1039/C6NP00080K
Other University of Auckland co-authors: Paul Hume, Jonathan Sperry
- De Leon-Rodriguez, L. M., Hemar, Y., Mo, G., Mitra, A. K., Cornish, J., & Brimble, M. A. (2017). Multifunctional thermoresponsive designer peptide hydrogels. Acta Biomaterialia, 47, 40-49. 10.1016/j.actbio.2016.10.014
Other University of Auckland co-authors: Yacine Hemar, Jillian Cornish, Alok Mitra, Luis De Leon Rodriguez
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