Peptides of the relaxin family and the protein enzyme insulin-regulated aminopeptidase (IRAP) are the major research themes of the Neuropeptides team.
Our long standing research focus on the relaxin peptide family and their receptors continues, with important advances in understanding peptide structure and function led by Professor John Wade, the role of relaxin in fibrosis by Dr Chrishan Samuel and receptor function and signalling from Associate Professor Ross Bathgate’s team. Studies on the novel neuropeptide relaxin-3 and its GPCR receptor RXFP3 have uncovered their potential role in the modulation of arousal, sleep/wake patterns, mood and memory. Relaxin-3 research is led by Associate Professor Andrew Gundlach, with strong collaborative support from Johnson & Johnson Pharmaceutical Research and Development (San Diego, CA). Studies on the physiological role of the enzyme known as IRAP have opened the way for the development of strategies for the treatment of memory disorders. Dr Siew-Yeen Chai and her colleagues have discovered a series of small molecule IRAP inhibitors with memory enhancing properties that have exciting potential for alleviating memory deficits.
The Relaxin Project continues its successful clinical development with ongoing Phase III trials in acute heart failure. This is the culmination of many years of research by Florey scientists investigating the biological role of the relaxin peptide family and is underpinned by a strong portfolio of international patents. The Phase II trial in acute heart failure showed strong, unequivocal improvement in heart function. Relaxin was safe and well tolerated and there was evidence of a protective effect on kidney function. The Phase III clinical trial involves 2,000 patients worldwide and will be completed in 2011. The US Food and Drug Administration (FDA) has granted "Fast Track¨ designation to relaxin as part of its program to expedite the review of new drugs intended to treat serious or life-threatening conditions that can potentially address unmet medical needs. In an exciting development in late 2009 our commercial partner, Corthera Inc (San Mateo, CA, formerly known as BAS Medical) was acquired by the large pharmaceutical company Novartis based in Switzerland.
The Neuropeptides team maintains its competitive position in the field internationally with key papers recently published in the Proceedings of the National Academy of Sciences USA, FASEB Journal, Molecular Pharmacology, Endocrinology, Journal of Comparative Neurology and Learning and Memory. Professor John Wade and Dr Sherie Ma were awarded Australian Academy of Science awards for research visits to Europe and many of Neuropeptide team students received travel awards to attend National and International meetings.
1. Andrew C. Rapson, Mohammed Akhter Hossain, John D. Wade, Edouard C. Nice, Trevor A. Smith, Andrew H. A. Clayton and Michelle L. Gee “Structural Dynamics of a Lytic Peptide Interacting with a Supported Lipid Bilayer”. Biophysical Journal. 2011; 100:1353-61. PMID: 21354409.
2. Fazel Shabanpoor, Suode Zhang, Richard Anthony Hughes, Mohammed Akhter Hossain, Sharon Layfield, Tania Faeearo, Ross A. D. Bathgate, Frances Separovic, and John D. Wade “Design and development of analogues of dimers of insulin-like peptide 3 (INSL3) B-chain as high affinity antagonists of the RXFP2 receptor”. Biopolymers. 2011; 96:81-7. PMID: 20560146.
3. Mohammed Akhter Hossain, Bryna Chow Suet Man, Chongxin Zhao, Qi Xu, Xiao-Jun Du, John D. Wade, Chrishan S. Samuel “H3 relaxin demonstrates anti-fibrotic properties via the RXFP1 receptor”. Biochemistry. 2011; 50:1368-75. PMID: 21229994.
4. Mohammed Akhter Hossain, Laure Guilhaudis, Agnes Sonnevend, Samir Attoub, Bianca J. van Lierop, Andrea J. Robinson, John D. Wade, and J. Michael Conlon “Synthesis, conformational analysis, and biological properties of a dicarba derivative of the antimicrobial peptide, brevinin-1BYa”. European Biophysics Journal. 2011; 40-555-564. PMID: 21312033.
5. Linda Haugaard-Kedström, Fazel Shabanpoor, Mohammed Akhter Hossain, Richard Clark, Philip Ryan, David Craik, Andrew Gundlach, John D Wade, Ross D Bathgate, K. Johan Rosengren “Design, Synthesis and Characterization of a Single-Chain Peptide Antagonist for the Relaxin-3 Receptor RXFP3”. Journal of the American Chemical Society. 2011; 133: 4965-4974. PMID: 21384867.
6. Alessis Belgi A, Mohammed Akhter Hossain, Fazel Shabanpoor, Linda Chan, Suode Zhang, Ross AD Bathgate, Geoffrey W Tregear GW, and John D. Wade “Structure and function relationship of murine insulin-like peptide 5 (INSL5): free C-terminus is essential for RXFP4 receptor binding and activation” Biochemistry. 2011; 50:8352-61. PMID: 21866895.
7. Zhang WJ, Luo X, Liu YL, Shao XX, Wade JD, Bathgate RA, Guo ZY “Site-specific DOTA/europium-labeling of recombinant human relaxin-3 for receptor-ligand interaction studies”. Amino Acids. 2011 Dec 21. [Epub ahead of print]. PMID: 22187146.
8. Linda J Chan, Mohammed Akhter Hossain, Chrishan S Samuel, Frances Separovic and John D Wade “The relaxin peptide family: structure, function and clinical application”. Protein and Peptide Letters. 2011; 18:220-9. PMID: 20858209.
9. Alessia Belgi, Mohammed Akhter Hossain, Geoffrey W. Tregear and John D. Wade “The Chemical Synthesis of Insulin: From the Past to the Present”. Immunology, Endocine & Metabolic Agents in Medicinal Chemistry. 2011; 11-40-47. PMID: Not listed.
10. Mohammed Akhter Hossain, K. Johan Rosengren, Chrishan S. Samuel, Fazel Shabanpoor, Linda J. Chan, Ross A.D. Bathgate, and John D. Wade “The minimal active structure of human relaxin-2”. Journal of Biological Chemistry. 2011; 286, 37555-65. PMID: 21878627.
11. Samuel CS, Cendrawan S, Gao XM, Ming Z, Zhao C, Kiriazis H, Xu Q, Tregear GW, Bathgate RA, Du XJ “Relaxin remodels fibrotic healing following myocardial infarction”. Lab Invest. 2011; 91:675-90. PMID: 21221074.
12. Olucha-Bordonau FE, Otero-García M, Sánchez-Pérez AM, Núñez A, Ma S, Gundlach AL “Distribution and targets of the relaxin-3 innervation of the septal area in the rat”. Comp Neurol. 2011; Dec 1. doi: 10.1002/cne.23018. PMID: 22134882.
13. Smith CM, Ryan PJ, Hosken IT, Ma S, Gundlach AL “Relaxin-3 systems in the brain--the first 10 years”. J. Chem. Neuroanat. 2011; 42:262-75. PMID: 21693186.
14. Ryan PJ, Ma S, Olucha-Bordonau FE, Gundlach AL “Nucleus incertus--an emerging modulatory role in arousal, stress and memory”. Neurosci Biobehav Rev. 2011; 35:1326-41. PMID: 21329721.
15. Huang X, Gai Y, Yang N, Lu B, Samuel CS, Thannickal VJ, Zhou Y. “Relaxin regulates myofibroblast contractility and protects against lung fibrosis”. Am J Pathol. 2011; 179:2751-65. PMID: 21983071.
16. Alikhan MA, Jones CV, Williams TM, Beckhouse AG, Fletcher AL, Kett MM, Sakkal S, Samuel CS, Ramsay RG, Deane JA, Wells CA, Little MH, Hume DA, Ricardo SD “Colony-stimulating factor-1 promotes kidney growth and repair via alteration of macrophage responses”. Am J Pathol. 2011; 179:1243-56. PMID: 21762674.
17. Otvos L Jr, Shao WH, Vanniasinghe AS, Amon MA, Holub MC, Kovalszky I, Wade JD, Doll M, Cohen PL, Manolios N, Surmacz E “Toward understanding the role of leptin and leptin receptor antagonism in preclinical models of rheumatoid arthritis”. 2011; 32:1567-74. PMID: 21723351.
18. Otvos L Jr, Kovalszky I, Riolfi M, Ferla R, Olah J, Sztodola A, Nama K, Molino A, Piubello Q, Wade JD, Surmacz E. “Efficacy of a leptin receptor antagonist peptide in a mouse model of triple-negative breast cancer” Eur J Cancer. 2011; 47(10):1578-84. PMID: 21353530.
19. Ostorhazi E, Holub MC, Rozgonyi F, Harmos F, Cassone M, Wade JD, Otvos L Jr. “Broad-spectrum antimicrobial efficacy of peptide A3-APO in mouse models of multidrug-resistant wound and lung infections cannot be explained by in vitro activity against the pathogens involved”. Int J Antimicrob Agents. 2011; 37:480-4. PMID: 21353493.
20. Shabanpoor F, Separovic F, Wade JD. “General method for selective labelling of double-chain cysteine-rich peptides with a lanthanide chelate via solid-phase synthesis”. J Pept Sci. 2011 (in press.). PMID: 21226031.
21. Ostorhazi E, Rozgonyi F, Szabo D, Binas A, Cassone M, Wade JD, Nolte O, Bethel CR, Bonomo RA, Otvos L Jr. “Intramuscularly administered peptide A3-APO is effective against carbapenem-resistant Acinetobacter baumannii in mouse models of systemic infections”. Biopolymers. 2011; 96:126-9. PMID: 20564029.
22. Otvos L Jr, Kovalszky I, Scolaro L, Sztodola A, Olah J, Cassone M, Knappe D, Hoffmann R, Lovas S, Hatfield MP, Beko G, Zhang S, Wade JD, Surmacz E. “Peptide-based leptin receptor antagonists for cancer treatment and appetite regulation”. Biopolymers. 2011; 96:117-25. PMID: 20564005.
23. Feugang JM, Rodriguez-Munoz JC, Willard ST, Bathgate RA and Ryan PL (2011) Examination of relaxin and its receptors expression in pig gametes and embryos. Reproductive Biology and Endocrinology 9:10 PMID: 21251292
Prof David Craik and Dr Johan Rosengren
Institute of Molecular Bioscience, University of Queensland
Tertiary structure determination of relaxin and INSL3 peptides
Dr Xiao-Jun Du
Baker Heart Research Institute, Melbourne
Role of relaxin in the heart and potential of relaxin as a treatment for cardiac fibrosis
Dr Marie Gibbs
Department of Anatomy and Cell Biology, Monash University
The role of astrocytes in learning and memory formation
A/Prof Paul Gooley
Department of Biochemistry and Molecular Biology, University of Melbourne
Structural studies on the relaxin family peptide receptors
Dr Tim Hewitson
Department of Nephrology, Royal Melbourne Hospital, Melbourne
Investigating the therapeutic potential of relaxin in interstitial renal fibrosis
Dr Tony Hughes
Department of Pharmacology, University of Melbourne
Design and synthesis of conformationally constrained mimetics of relaxin and INSL3
Prof John Hutson
Douglas Stephens Surgical Laboratory, Murdoch Children’s Research Institute, Melbourne
The role of RLF (INSL3) in gubernacular development
Prof Richard Ivell
School of Molecular and Biomedical Sciences, University of Adelaide
Biology of INSL3
Prof Michael Parker
St Vincent’s Institute of Medical Research, Melbourne
Understanding protein structure of IRAP and its interactions with inhibitors
A/Prof Ray Rogers
Reproductive Medicine Unit, Department of Obstetrics and Gynecology, University of Adelaide
The function of ovarian follicular INSL3
Prof Roger Summers
Department of Pharmacology, Monash University
Relaxin receptor signaling
A/Prof Mimi Tang
Department of Allergy and Immunology, Murdoch Children’s Research Institute, Melbourne
Investigating the therapeutic effects of relaxin on airway remodeling and function
Prof Walter Thomas
School of Biomedical Sciences, University of Queensland
Viral strategies for studying relaxin peptide function
Dr Phillip Thompson
Department of Medicinal Chemistry, Monash University
Design of small molecule IRAP inhibitors
Dr Jose Villadangos
Walter and Eliza Hall Institute
Role of IRAP in antigen cross presentation
Dr Anthony White
Department of Pathology, University of Melbourne
Role of IRAP in Alzheimer’s disease
A/Prof Tony Verberne
Department of Medicine, Austin and Northern Health, University of Melbourne
Relaxin-3 systems in the brain: Neurophysiology and behaviour
Drs Robert Widdop and Tracey Gaspari
Department of Pharmacology, Monash University
Investigations into the cardiovascular function of the IRAP knockout mouse
Dr Edward Amento
Molecular Medicine Research Institute, San Francisco, USA
Relaxin and extracellular matrix biology
Dr Anna Blasiak and Dr Tomasz Blasiak
Department of Neurophysiology & Chronobiology, Jagiellonian University, Krakow, Poland
Relaxin-3 systems and biorhythms
Dr Marco Capagno
MRC Anatomical Neuropharmacology Unit, Oxford, UK
Cellular physiology of relaxin-3 in amygdala
Prof Alon Chen
Department of Neurobiology, Weizmann Institute of Science, Rehovot, Israel
Prof Andrew Lawrence
The Florey Institute of Neuroscience and Mental Health
Interaction of relaxin-3 and CRF systems
A/Prof Gavin Dawe
Department of Pharmacology, National University of Singapore, Singapore
Relaxin-3 systems in adult neurogenesis and hippocampal function
Prof Pierre De Meyts
Receptor Systems Biology Laboratory, Hagedorn Research Institute, Denmark
Dimerization of relaxin family peptide receptors
Prof Aaron Hsueh
Division of Reproductive Biology, Department of Gynecology and Obstetrics, Stanford University Medical Centre, Stanford University, CA, USA
Defining the structural domains of the LGR7 and LGR8 receptors and determining the functions of INSL3 in the gonads
Dr Patrick Kehoe
Department of Clinical Science at North Bristol, University of Bristol, Frenchay Hospital, Bristol, UK
IRAP gene polymorphism and Alzheimer’s disease
Dr Jose Lanciego
Neurosciences Division, CIMA, University of Navarra, Pamplona, Spain
Comparative studies of relaxin-family peptides and receptors in non-human primate
Dr Tim Lovenberg
Pharmaceutical Research and Development, Johnson and Johnson, San Diego, USA
Distribution, regulation and function of relaxin-3 and GPCR135 in the brain
Prof Thomas McCown
Department of Psychiatry, University of North Carolina, Chapel Hill, NC, USA
Viral strategies for studying relaxin-3 function
Dr Ewan McNay
Section of Endocrinology, Yale University School of Medicine, New Haven, CT, USA
Role of IRAP in modulating brain glucose uptake
Professor Yvette Michotte, Professor Ilse Smolders and Dr Patrick Vanderheyden
Vrije University, Brussels, Belgium
Characterisation of the global and tissue specific IRAP Knockout mouse
Dr Sietse Mosselman and Dr Anne Riesewijk
Department of Pharmacology, NV Organon, The Netherlands
Phenotyping the LGR7 KO mouse and cloning and characterising rodent LGR7 genes
A/Prof Angel Nunez
Department of Anatomy, Histology & Neuroscience, University Autonoma Madrid, Madrid, Spain
Nucleus incertus and relaxin-3 in theta rhythm generation
A/Prof Francisco Olucha-Bordonau
Department of Human Anatomy and Embryology, University of Valencia, Valencia, Spain
Anatomy and function of nucleus incertus and relaxin-3 pathways
Prof Lazlo Otvos Jr
The Wistar Institute, Philadelphia, USA
Structural analyses of relaxin and INSL3
Prof David Sherwood
Department of Molecular and Integrative Physiology, University of Illinois, USA
Studies on rodent relaxin receptors
Dr Dennis Stewart and Dr Elaine Unemori
BAS Medical, San Mateo, USA
Development of relaxin as an antifibrotic drug
Prof Masafumi Tsujimoto
Lab of Cellular Biochemistry, RIKEN, Saitama, Japan
Characterisation of aminopeptidase activity
Prof Georges Vanquelin
Department of Molecular and Biochemical Pharmacology, Vrije Universiteit Brussel, Belgium
Role of IRAP in immune cells and on neurotransmitter release