Prof Dame Margaret Anne Brimble

MSc (Auckland), PhD (Southampton, UK)

Biography

Dame Margaret Brimble FRS is a Distinguished Professor and Director of Medicinal Chemistry at the University of Auckland, New Zealand. She is an Associate Editor for Organic Letters, Deputy Director of the Maurice Wilkins Centre for Molecular Biodiscovery and Past-President of IUPAC Organic and Biomolecular Division III. She is a Fellow of the Royal Society London, Dame Companion of the New Zealand Order of Merit, has been inducted into the American Chemical Society Medicinal Chemistry Hall of Fame and received the Rutherford, Hector and MacDiarmid medals (Royal Society NZ), the Kiwinet BNZ Supreme award and Baldwins Research Entrepreneur 2019 commercialization awards and the Marsden medal (NZ Association of Scientists). She was awarded the Sosnovsky Award for Cancer Therapy and Natural Products award from the Royal Society of Chemistry. Her research focusses on the synthesis of novel bioactive natural products/antimicrobial peptides and the synthesis of lipopeptides for cancer vaccines and new biomaterials. She discovered the drug candidate trofinetide (NNZ2566) that was successful in phase 3 clinical trials for Rett Syndrome (Neuren Pharmaceuticals and Acadia Pharmaceuticals; FDA approval in 2022) and NNZ2591 (phase 2 clinical trials for Phelan-McDermid syndrome, Angelman syndrome,  Pitt Hopkins syndrome and Prader-Willi syndrome). She is co-founder of the cancer immunotherapy company SapVax that has licensed her CLipPA peptide lipidation technology to develop self-adjuvanting peptide-based cancer vaccines.  Her laboratory hosts NZ’s only laboratory accredited by Medsafe NZ to manufacture peptides under cGMP for human clinical trial. 

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 (named trofinetide by the WHO) for Neuren Pharmaceuticals that was successful in phase 3 clinical trials for Rett Syndrome (FDA approval pending in 2022). Our group has also discovered a second drug candidate NNZ2591 for Neuren entering phase 2 clinical trials for Phelan-McDermid, Angelman, Pitt Hopkins and Prader-Willi Syndromes, four debilitating neurodegenerative disorders with no approved treatments. Trofinetide and NNZ2591 have been granted fast track and orphan drug status by the FDA.

 Profesor Brimble is also co-Founder of the cancer immunotherapy SapVax.llc that has licensed her CLipPA peptide lipidation technology to develop self-adjuvanting peptide-based cancer vaccines.  Our laboratory has also been licensed by medsafe NZ 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.

Our group also contributes to collaborative agrochemistry programmes focused on development of methanogen inhibitors, nitrification inhibitors, rat selective toxicants and new generation sanitizers.

Current projects

Find more information about Margaret's research on the Brimble Group website.

Teaching | Current

Director of BSc Hons Medicinal Chemistry Programme

Postgraduate supervision

Curently supervising 10 PhD students in natural products synthesis and 10 PhD students in peptide chemistry (with Assoc. Prof Paul Harris).

Distinctions/Honours

2019   Queen’s Honour–Dame Companion New Zealand Order of Merit (DNZM).

            Inducted into American Chemical Society Medicinal Chemistry Hall of Fame

            Supreme Award Kiwinet Research Commercialisation Awards

            Research Entrepreneur Award Kiwinet Research Commercialisation Awards

             Zonta Centenary Women of Achievement Award

2018   Elected Fellow of The Royal Society (FRS)–first female New Zealander.

            Royal Society Chemistry. George & Christine Sosnovsky Award in Cancer Therapy.

2017   IUPAC Award–Outstanding Service in Advancement of Chemistry Worldwide.

2016   NZ Assoc. of Scientists Marsden Medal (Lifetime Achievement in Science)

           Royal Society of Chemistry Australasian Lectureship.

2015   IUPAC Distinguished Women in Chemistry/Chemical Engineering Award.

            Senior Fellowship Award International Society of Heterocyclic Chemistry.

            University of Auckland Vice-Chancellor’s Commercialization Medal.

2014   Westpac Trust Women of Influence Award (Science and Innovation).

2012   Queen’s Honour–Companion New Zealand Order of Merit (CNZM).

            RSNZ Rutherford Medal (top science medal)

            RSNZ Hector Medal (Chem.Sciences)

            RSNZ MacDiarmid Medal (Human Benefit)

2011   Royal Australian Chem. Inst. Adrien Albert Award (Medicinal Chemistry).

            Dean’s Award for postgraduate supervision; RSNZ Marie Curie lectureship.

2010   Royal Society of Chemistry UK Natural Products Chemistry Award

2008   World Class NZ Award (Research, Science, Technology & Academia).

2007   L'ORÉAL-UNESCO Women in Science Laureate Asia/Pacific.

2005   NZIC HortResearch Prize for Excellence in the Chemical Sciences.

2004   Queen’s Honour–MNZM; RSNZ James Cook Research Fellowship.

2003   Novartis Chemistry Prize; Royal Society Rosalind Franklin Lectureship.

2001   Federation of Asian Chemical Societies Distinguished Chemist Award.

1992   NZIC Easterfield Medal; RSNZ Hamilton Memorial Prize.

 

Responsibilities

Associate Editor for Organic Letters (American Chemical Society)

Deputy Director Maurice Wilkins Centre for Molecular Biodiscovery ( a National Centre of Research Excellence)

Co-Founder SapVax.llc

Areas of expertise

Expertise

Inventor Trofinetide (NNZ2566) – robust results in phase 3 clinical trials for Rett Syndrome (Neuren Pharmaceuticals and Acadia Pharmaceuticals), FDA approval pending 2022;

Inventor – NNZ2591; enteing phase 2 clinical trials in 4 rare neurogenetic disorders:Phelan-McDermid syndrome, Angelman syndrome, Pitt Hopkins syndrome and Prader-Willi syndrome.

Organic Synthesis; Medicinal Chemistry; Drug Development; Natural Products; Agrochemistry; GMP synthesis peptide cancer vaccines; Co-Founder SapVax.llc);

Consultant/Expert Witness - several international pharmaceutical companies.

Interests: Synthesis of: bioactive natural products and traditional Chinese medicines; norovirus and SarsCov2 mPro protease inhibitors; telomerase inhibitors; antimicrobial peptides; cell penetrating peptides; lipopeptides; peptidomimetics; alkaloids as neuroprotective agents; antibody-drug conjugates; 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.

20 Selected Publications 

NATURAL PRODUCTS SYNTHESIS AND SYNTHETIC METHODOLOGY

1.    “Asymmetric Total Synthesis of the Naturally Occurring Antibiotic Anthracimycin” E. K. Davison, J. L. Freeman, W. Zhang, W. M. Wuest, D. P. Furkert and M. A. BrimbleOrganic Letters202022, 22, 5550-5554.  (IF = 6.6)

2.    “Highly Diastereoselective Synthesis of syn-1,3-Dihydroxyketone Motifs from Propargylic Alcohols via Unusual Spiroepoxide Intermediates” X. Ding, D. P. Furkert and M. A. BrimbleAngewandte Chemie International Edition201958, 11830-11835. (IF = 12.1)

3.    Bioinspired Total Synthesis and Stereochemical Revision of the Fungal Metabolite Pestalospirane B” S. Badrinarayanan, C. J. Squire, J. Sperry and M. A. Brimble, Organic Letters201719, 3414-3417.  (IF = 6.3) 

Selected for inclusion in ACS Select Collection focused on Natural Products Total Synthesis because of its high scientific quality and broad appeal.

4.    “Unexpected Direct Synthesis of N-Vinyl Amides Through Vinyl Azide-Enolate [3+2] Cycloaddition” H. Choi, H. J. Shirley, P. A. Hume, D. P. Furkert and M. A. Brimble, Angewandte Chemie International Edition201756, 7420-7424. (IF = 12.0) Selected by Editorial Board of Synfacts for its important insights; see: Synfacts 201713(08), 0864; DOI: 10.1055/s-0036-1590632; Contributors: P.Knochel, J. M. Hammann

5.    “General Synthesis of the Nitropyrrolin Family of Natural Products via Regioselective CO2-Mediated Alkyne Hydration” X.-B. Ding, D. P. Furkert and M. A. Brimble, Organic Letters201719, 5418-5421. (IF = 6.6). Selected for inclusion in Organic Highlights:  https://www.organic-chemistry.org/Highlights/2018/28May.shtm

6.    “Total Synthesis of Virgatolide B” P. A. Hume, D. P. Furkert and M. A. Brimble, Organic Letters201315, 4588-4591. (IF = 6.1)

7.    “Total Synthesis of 7',8'-Dihydroaigialospirol” T. Y. Yuen and M. A. Brimble, Organic Letters201214, 5154-5157. (IF = 6.1)

8.    “An Enantioselective Formal Synthesis of Berkelic Acid”  M. C. McLeod, Z. E. Wilson and M. A. Brimble, Organic Letters, 201113, 5382-5385. (IF = 6.1)

9.    “Total Synthesis of Paecilospirone” T.-Y. Yuen, S.-H. Yang and M. A. Brimble, Angewandte Chemie International Edition201150, 8350-8353. (IF = 13.5)

10.  “An Efficient Formal Synthesis of the Human Telomerase Inhibitor (±)-γ-Rubromycin”  D. C. K. Rathwell, S.-H. Yang, K. Y. Tsang and M.A. Brimble, Angewandte Chemie International Edition200948, 7996-8000. (IF = 11.8) Selected for Frontispiece and as a VIP paper, <5% of accepted papers receive this accolade. The paper was also discussed on the “Totally Synthetic” blog site where it was described as one of the most elegant syntheses to be reported and it received over 8000 views (see: http://www.organic-chemistry.org/totalsynthesis/totsyn05/rubromycin-brimble.shtm )

PEPTIDE AND PEPTIDOMIMETIC CHEMISTRY

11.  “On-Resin Preparation of Allenamidyl Peptides: A Versatile Chemoselective Conjugation and Intramolecular Cyclisation Tool” A. Cameron, P.W.R. Harris and M. A. Brimble, Angewandte Chemie International Edition202059, https://doi.org/10.1002/anie.202004656. (IF = 12.1) Selected for Back Cover Image and as a VIP paper/Hot Article, <5% of accepted papers receive this accolade; see: https://doi.org/10.1002/anie.202011912.

12.  “A Synthetic Approach to ‘Click’ Neoglycoprotein Analogues of EPO Employing One-pot Native Chemical Ligation and CuAAC Chemistry” D. J. Lee, A. J. Cameron, T. H. Wright, P. W. R. Harris and M. A. Brimble, Chemical Science201910, 815-828. (IF = 9.1) Highlighted in Chemistry World: “Erythropoietin Benefits from Controlled Sugar-Coating” by  L. Ghandhi, (see: https://www.chemistryworld.com/news/erythropoietin-benefits-from-controlled-sugar-coating/3009861.article)

13.  “Total Synthesis and Conformational Study of The Anti-tubercular Cyclic Peptide Callyaerin A Bearing a Rare Rigidifying (Z)-2,3-Diaminoacrylamide Moiety” M. A. Brimble, S. Zhang, L. M. De Leon Rodriguez, I. K. H. Leung, G. M. Cook and  P. W. R. Harris, Angewandte Chemie International Edition201857, 3631-3635. (IF = 12.1. Selected for Front Cover Image and as a VIP paper, <5% of accepted papers receive this accolade; highlighted on ChemistryViews.org http://www.chemistryviews.org/details/ezine/10879614/Total_Synthesis_of_Callyaerin_A.html

14.  “Genome Mining, Isolation, Chemical Synthesis and Biological Evaluation of a Novel Lanthipeptide, Tikitericin and N-Truncated Analogues, from the Extremophilic Microorganism Thermogemmatispora Strain T81” B. Xu, E. J. Aitken, B. P. Baker, C. Turner, J. E. Harvey, M. B. Stott, J. F. Power, P. W.R. Harris, R. A. Keyzers and M. A. Brimble, Chemical Science20189, 7311-7317. (IF = 9.1) Selected as Article for Chemical Science “Pick of the Week” and as Back Cover

15. “Solid-Phase Thiol-ene Lipidation of Peptides for the Synthesis of a Potent CGRP Receptor Antagonist” E.T. Williams, P.W.R. Harris, M.A. Jamaluddin, K.M. Loomes, D.L. Hay and M.A. Brimble, Angewandte Chemie International Edition201857, 11640-11643. (IF = 12.1)

16.  “Total Chemical Synthesis of Glycocin F and Analogues: S-Glycosylation Confers Improved Antimicrobial Activity” Z. Amso, S. W. Bisset, S.-H. Yang, P. W. R. Harris, T. H. Wright, C. D. Navo, M. L. Patchett, G. E. Norris and M. A. BrimbleChemical Science20189, 1686-1691. (IF = 9.1)

17.  “Radiation Damage and Racemic Crystallography Reveal the Unique Structure of the GASA/Snakin Protein Superfamily” H. Yeung, C. J. Squire, Y. Yosaatmadja, S. Panjikar, G. López, A. Molina, E. N. Baker, P. W. R. Harris and M. A. Brimble, Angewandte Chemie International Edition201655, 7930-7933. (IF = 11.3) Selected for the Front Cover Image and as a VIP paper, <5% of accepted papers receive this accolade. Featured in Chemistry in Australia, “Elusive Potato Protein Structure Solved,” September issue 2016, p 11.

18.  “Synthesis and Activity of a Diselenide Bond Mimetic of the Antimicrobial Protein Caenopore‑5” K. Medini, P. W. R. Harris, A. Menorca, K. Hards, G. M. Cook and M. A. Brimble, Chemical Science, 20167, 2005-2010. (IF = 9.2) 

19.  “Total Synthesis of the Cyclic Depsipeptide YM-280193, a Platelet Aggregation Inhibitor” H. Kaur, P. W. R. Harris, P. J. Little and M.A. Brimble, Organic Letters201517, 492-495. (IF = 6.3) The work reported in this paper was subsequently acknowledged by several publications in top journals including Nature Chemistry20168, 1035-1041. 

 20.  “Direct Peptide Lipidation through Thiol-ene Coupling Enables Rapid Synthesis and Evaluation of Self adjuvanting Vaccine Candidates” T.H. Wright, A.J. Didsbury, G.M. Williams, P.W.R. Harris, R.P. Dunbar and M. A. Brimble, Angewandte Chemie International Edition, 201352, 10616-10619. (IF = 13.7)

Committees/Professional groups/Services

Distinguished Professor, Chair of Organic and Medicinal Chemistry, Director of Medicinal Chemistry, Deputy Director Maurice Wilkins Centre for Molecular Biodiscovery, Past-Chair of the Royal Society of New Zealand Rutherford Foundation, Past-President of Organic and Biomolecular Division of the International Union of Pure and Applied Chemistry, Past-President International Society of Heterocyclic Chemistry,  Member of the European Research Council PE5 panel for Synthetic Chemistry and Materials Science.

 

Selected publications and creative works (Research Outputs)

As of 29 October 2020 there will be no automatic updating of 'selected publications and creative works' from Research Outputs. Please continue to keep your Research Outputs profile up to date.
  • Gaar, J., Naffa, R., & Brimble, M. (2020). Enzymatic and non-enzymatic crosslinks found in collagen and elastin and their chemical synthesis. ORGANIC CHEMISTRY FRONTIERS, 7 (18), 2789-2814. 10.1039/d0qo00624f
  • Dissanayake, S. S. M., Ekambaram, M., Li, K. C., Harris, P. W. R., & Brimble, M. A. (2020). Identification of Key Functional Motifs of Native Amelogenin Protein for Dental Enamel Remineralisation. Molecules (Basel, Switzerland), 25 (18).10.3390/molecules25184214
    Other University of Auckland co-authors: Paul Harris
  • Ko, K.-Y., Wilson, Z. E., Furkert, D. P., & Brimble, M. A. (2020). A Ring Closing Metathesis Approach to the Formal Synthesis of (+)-Callyspongiolide. CHEMCATCHEM10.1002/cctc.202001139
    Other University of Auckland co-authors: Zoe Wilson, Dan Furkert
  • Yang, S.-H., Clemett, C. A., Brimble, M. A., O'Carroll SJ, & Harris, P. W. R. (2020). Synthesis and biological evaluation ofS-lipidated lipopeptides of a connexin 43 channel inhibitory peptide. RSC MEDICINAL CHEMISTRY, 11 (9), 1041-1047. 10.1039/d0md00172d
    Other University of Auckland co-authors: Simon OCarroll, Paul Harris
  • Rani, A., Kavianinia, I., De Leon-Rodriguez, L. M., McGillivray, D. J., Williams, D. E., & Brimble, M. A. (2020). Nanoribbon self-assembly and hydrogel formation from an NOctanoyl octapeptide derived from the antiparallel β-Interface of a protein homotetramer. Acta biomaterialia, 114, 233-243. 10.1016/j.actbio.2020.07.023
    Other University of Auckland co-authors: David Williams, Duncan McGillivray
  • Yim, V. V., Cameron, A. J., Kavianinia, I., Harris, P. W. R., & Brimble, M. A. (2020). Thiol-ene Enabled Chemical Synthesis of TruncatedS-Lipidated Teixobactin Analogs. FRONTIERS IN CHEMISTRY, 810.3389/fchem.2020.00568
  • Li, F. F., Stubbing, L. A., Kavianinia, I., Abbattista, M. R., Harris, P. W. R., Smaill, J. B., ... Brimble, M. A. (2020). Synthesis and antiproliferative activity of C- and N-terminal analogues of culicinin D. Bioorganic & medicinal chemistry letters, 30 (16)10.1016/j.bmcl.2020.127331
    Other University of Auckland co-authors: Louise Stubbing, Freda Li, Iman Kavianinia, Paul Harris, Jeff Smaill, Adam Patterson
  • Wang, Y., Yang, S. H., Brimble, M. A., & Harris, P. W. R. (2020). Recent Progress in the Synthesis of Homogeneous Erythropoietin (EPO) Glycoforms. CHEMBIOCHEM10.1002/cbic.202000347
    Other University of Auckland co-authors: Paul Harris

Identifiers

Contact details

Alternative contact

Correct Location:
SCIENCE CENTRE 301
Level 7, Room 301-731B
23 SYMONDS ST
Auckland 1010
New Zealand

Primary office location

SCIENCE CENTRE - CHEMISTRY - Bldg 301
Level 7, Room 731B
23 SYMONDS ST
AUCKLAND 1010
New Zealand

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