PhD student profiles

     
     
Paul Moody

Paul Moody
Paul joined the ISMB's Wellcome Trust 4-year Interdisciplinary PhD Programme in Autumn 2009

Project title
Evaluation of strategies for the modular design of therapeutics and diagnostics

Principal investigator: Professor Stephen Caddick, Department of Chemistry, UCL
Co-investigators: Dr Justin Molloy, NIMR

   
Background
Since my undergraduate project, I became interested in protein design, and so I was excited to take part in a PhD programme that provides training in computational and chemical biology. The first year rotations enabled me to learn and apply new techniques such as crystallography, chemical modifications of proteins, and computational protein design. My research has also benefited from building contacts with researchers from many different backgrounds. I studied for a Masters in Biochemistry at Oxford university, where I did a 4th year project with Dr. Mark Howarth.
 

Rotations

Professor Nick Keep

  • Co-crystalised TB MurE with a novel ligand combination
  • Solved, refined and published the novel structure 2xja
  • Truncation of the N-terminal fragment of TB MurE for improved crystal packing

Professor Willie Taylor

  • Unpublished work

Professor Stephen Caddick

  • See below
 
PhD Project
During my rotation and subsequent PhD project with Professor Caddick, I have been evaluating various strategies for the generation of targeted therapeutics. Initially we generated FRET constructs around multifunctional bromomaleimide linkers, and demonstrated that these linkers were able to release cargo inside cells. Unfortunately, fluorescence microscopy of live cells demonstrated that cargo was also released at the cell surface. The second strategy involved the use of neocarzinostatin, a potential multifunctional therapeutic. Neocarzostatin is themostable protein that has been reported to functionally display antibody binding loops, and to internalise and release its cargo into mammalian cells. We aimed to demonstrate if the recombinantly expressed apoprotein could also internalise into cells. Analysis by fluoresence microscopy and MALDI mass spectrometry demonstrated that this was not the case. The final strategy that we have been evaluating is the dual modification of proteins by a novel strategy, for which we have filed a patent.
 

figure

Artwork by Hayley Wood (MRC NIMR) and Dr Rachel Morgan (UCL)
 
Publications

Reversible protein affinity-labelling using bromomaleimide-based reagents. Nathani RI, Chudasama V, Ryan CP, Moody PR, Morgan RE, Fitzmaurice RJ, Smith ME, Baker JR, Caddick S. Org Biomol Chem. 2013 Apr 21;11(15):2408-11

Evaluating the use of Apo-neocarzinostatin as a cell penetrating protein.Moody P, Burlina F, Martin SR, Morgan RE, Offer J, Smith ME, Molloy JE, Caddick S. Protein Eng Des Sel. 2013 Apr;26(4):277-81.

Bioconjugation of green fluorescent protein via an unexpectedly stable cyclic sulfonium intermediate. Nathani R, Moody P, Smith ME, Fitzmaurice RJ, Caddick S. Chembiochem. 2012 Jun 18;13(9):1283-5.

Bromomaleimide-linked bioconjugates are cleavable in mammalian cells.Moody P, Smith ME, Ryan CP, Chudasama V, Baker JR, Molloy J, Caddick S. Chembiochem. 2012 Jan 2;13(1):39-41.

Essential residues for the enzyme activity of ATP-dependent MurE ligase from Mycobacterium tuberculosis. Basavannacharya C, Moody PR, Munshi T, Cronin N, Keep NH, Bhakta S. Protein Cell. 2010 Nov;1(11):1011-22.

Electrophilic affibodies forming covalent bonds to protein targets. Holm L, Moody P, Howarth M. J Biol Chem. 2009 Nov 20;284(47):32906-13.

 

 

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