PhD Student, FT-ICR Mass Spectrometry Group

Started November 2015

Graduated January 2020

FT-ICR MS Group
Department of Chemistry
The University of Warwick
Millburn Hill Road
Coventry CV4 7AL, UK
Office: +44 (0) 24 7615 1304
Lab: +44 (0) 24 7615 1305

ORCID QR Code:

ORCID ID: 0000-0001-6967-7675

Email: K.C.Chiu@warwick.ac.uk

PhD Project

Detailed characterisation of novel metal-based drugs interactions with biomolecules by high resolution tandem mass spectrometry

With the aid of ultra high resolution mass spectrometry, to study the mechanism of action of organometallic metal-based anticancer drugs with a whole range of biomolecules, including peptides, proteins, DNA, and cell lysate.

Collaborative projects between the O'Connor and Sadler groups at the University of Warwick, Coventry, United Kingdom.

Project Background

Metal-based anticancer drugs (Metallo-drugs) such as cisplatin, are highly effective and widely used to treat various types of cancer. However, subsequent development of platinum resistance leads to treatment failure and low survival rates due to the reduced effectiveness after repeat dosing. Therefore, new metal-based anticancer drugs, designed to act against cancer via different mechanisms of action are being developed. We are focusing on the development of organometallic compounds that may be active towards cisplatin-resistant cancers and express fewer side effects compared with traditional platinum drugs.

Mass Spectrometry of metal complexes (metallo-drugs) is usually very different than that of the biomolecules modified with bare metal ions (such as Na+, Ag+, Cu2+, etc.). Also, with the nature of various different isotopes of the metals, the isotopic distribution of metal complexes with peptides and proteins appear to be very different to the usual distribution of bare peptides and proteins. Tandem mass spectrometry (MS/MS) of metal complexes bound molecules are observed to be more challenging due to the conformational changes of the metallo-drugs, asymmetric charge distribution, unique side chain losses, metal-induced sequence scrambling and a whole range of different modifications to the biomolecules.

With the application of different tamdem mass spectrometry techniques, such as electron capture dissociation (ECD), collisionally activated dissociation (CAD), infrared multi-photon dissociation (IRMPD), infrared electron capture dissociation (IR-ECD), etc, modification sites on biomolecules are investigated and characterised carefully.

We are now investigating a range of metal-based therapeutics to study their binding locations, and identities. We are currently investigating Platinum, Iridium, Ruthenium, Osmium, Gold, and Rhodium complexes but will be looking into many more in the future.

We are looking into different mechanism of actions towards cancer cells, such as photodynamic therapy, trying to a new angle of attack to cancer.

Please feel free to email me at K dot C dot Chiu at warwick dot ac dot uk if you have any questions about Top down peptide/protein fragmentations, Metal-biomolecule MS/MS, or our work in general.

Publications

• Alessandro Del Grosso, Lavrentis-Dimitrios Galanopoulos, Cookson K. C. Chiu, Guy J. Clarkson, Peter B. O'Connor, Martin Wills, Strained alkynes derived from 2,2′-dihydroxy-1,1′-biaryls; synthesis and copper-free cycloaddition with azides, Organic & Biomolecular Chemistry, 2017, 15, 4517-4521, DOI: 10.1039/C7OB00991G

 

• Pingyu Zhang and Cookson K. C. Chiu, Huaiyi Huang, Yuko P. Y. Lam, Abraha Habtemariam, Thomas Malcomson, Martin J. Paterson, Guy J. Clarkson, Peter B. O'Connor, Hui Chao, and Peter J. Sadler, Organoiridium Photosensitizers Induce Specific Oxidative Attack on Proteins within Cancer Cells, Angewandte Chemie International Edition, 2017, 56, 14898-14902, DOI: 10.1002/anie.201709082; Angewandte Chemie International Edition Inside Cover: DOI: 10.1002/anie.201710973

• Yuko P. Y. Lam, Christopher Wootton, Ian Hands-Portman, Juan Wei, Cookson K. C. Chiu, Isolda Romero-Canelon, Mark Barrow, Frederik Lermyte, and Peter O'Connor, Does Deamidation of Islet Amyloid Polypeptide Accelerate Amyloid Fibril Formation?, Chemical Communications, 2018, 54, 13853-13856, DOI:10.1039/C8CC06675B

 

• Christopher A. Wootton, Adam Millett, Andrea Lopez, Cookson K. C. Chiu, Mark Barrow, Guy J Clarkson, Peter J Sadler and Peter O' Connor. Structural analysis of peptides modified with organo-iridium complexes, opportunities from multi-mode fragmentation. Analyst, 2019, 144, 1575-1581, DOI: 10.1039/C8AN02094A

• Raul Berrocal-Martin, Carlos Sanchez-Cano, Cookson K. C. Chiu, Russell J. Needham, Peter J. Sadler, and Steven W. Magennis. Metallation-Induced Heterogeneous Dynamics of DNA Revealed by Single-Molecule FRET. Chemistry A European Journal, 2020, 26, 4980-4987, DOI: 10.1002/chem.202000458；Chemistry–A European Journal Cover, DOI: 10.1002/chem.202000769

• Yuko P. Y. Lam, Christopher A. Wootton, Ian Hands-Portman, Juan Wei, Cookson K. C. Chiu, Isolda Romero-Canelon, Mark Barrow, Frederik Lermyte, and Peter O'Connor, Determination of the Aggregate Binding Site of Amyloid Protofibrils Using Electron Capture Dissociation Tandem Mass Spectrometry. Journal of the American Society for Mass Spectrometry, 2020, 31, 267-276, DOI: 10.1021/jasms.9b00053

• Cookson K. C. Chiu, Yuko P. Y. Lam, Christopher A. Wootton, Mark P. Barrow, Peter J. Sadler, and Peter B. O'Connor, Metallocomplex-Peptide Interactions Studied by Ultrahigh Resolution Mass Spectrometry. Journal of the American Society for Mass Spectrometry, 2020, 31, 594-601, DOI:10.1021/jasms.9b00054

• Yuko P. Y. Lam, Cookson K. C. Chiu, Christopher A. Wootton, Ian Hands-Portman, Meng Li, Mark P. Barrow, and Peter B. O'Connor, Does deamidation affect inhibitory mechanisms towards amyloid protein aggregations? Chemical Communications, 2020, 56, 9787-9790, DOI: 10.1039/d0cc03548c

Press Releases

• Cancer cells destroyed with dinosaur extinction metal, please find links here (WorldPharmaNews), here (PharmaNews.EU), and here (Warwick News).
• ChemistryViews.org - Photoactive Iridium Complexes for Cancer Therapy

Application Notes and Patents

• Application note "Monitoring the Electrochemical Reduction of Disulphide Bonds in Proteins for Enhanced MS and MS/MS Capabilities". Christopher A. Wootton and Cookson Chiu, Agnieszka Kraj, Thomas Lambert, Simon Lambert, and Peter B. O’Connor, in collaboration with ARC Sciences (UK) and Antec (Netherlands), please find online here.
• Patent for novel ionisation source, O'Connor P.B., Wootton C.A., Hussein H., Chiu C., Wong M.

Conferences

Poster Presentations