A review of group publications for 2013

2013 has been a difficult year for many in the group, which makes it all the more remarkable that it was one of the most productive on record. In this era of ‘early view’ of papers I’m not as yet sure of the precise number, but it will be at least 12 peer review publications for 2013.

Work on protein modification featured again very heavily in the year and the group has a long-standing interest in the bacterial protein apo-Neocarzinostatin, an intriguing system, that has potential as a drug delivery system. Paul Moody, a joint student with NIMR, completed a painstaking study on the ability of modified NCS  constructs to undergo internalisation in mammalian cells (PEDS)

In another collaborative study with Derek Macmillan, in UCL Chemistry, Rachel Morgan generated a variety of  ubiquitin cysteine mutants that were studied in order to develop an exciting approach to c-terminally labelled proteins (Angew Chemie).

A key area of current research for the lab is in in reversible chemical modification of proteins employing cysteine modification and in 2013 excellent progress was again made. Early in the year we published a full paper in OBC describing a detailed study on the use of bromomaleiimide agents. Amongst the many practical observations made in this paper – we were delighted with the finding that we could reverse the modification using a bis-thiol under mild conditions.

We were also very pleased with a new approach to dual labelling which followed on from extensive work pioneered by Ramiz Nathani and Paul Moody. In a paper in Chemical Science, they described their fndings that a double cysteine mutant of superfolder GFP, showed differential reactivity. Thus it was possible to install two different functional groups onto two cysteines present in a protein.

The other main thrust of our lab is in the area of antibody modification in a close and very productive collaboration with the Baker group. In a very detailed study in conjunction with a number of colleagues across UCL, a new approach to monitoring antibody-antigen interactions was described in Scientific Reports. Felix Schumacher and Vischel Sanchania developed  spinostics, an approach which relies on the installation of an EPR probe – via disulphide insertion – and then monitoring using EPR.

Much of the work we do on protein and antibody modification is reliant on developing effective linker systems and we were delighted to disclose a new acid cleavable linker system in Chemical Communications. Pioneered by Mark Smith and Lourdes Castenada  the new thiomaleamic acid linker was designed so that it was stable at physiological pH and temperature, but quantitatively cleaves at lysosomal pH to release the drug payload. The strategy was illustrated using by insertion of the novel linker into the single interchain disulfide bond of a trastuzumab Fab fragment.

One of the key requirements for our protein and antibody work, is effective methods for making the most effective small molecules for attachment to biomolecules and a series of new and mild synthetic protocols for the synthesis of modified maleimides and pyridizadine-diones were also described this year.

But not all of our work was on proteins and antibodies. We continued our very productive collaboration with Frank King on heterocyclic chemistry.  This year we published a number of exciting acid mediated cyclisation methods for benzyl-cinnamanilides and naphthylamines providing access to interesting and novel multi-cyclic heterocycles.

Remaining with the field of cyclisations, Joao Nunes completed a detailed study related to our long standing interest in furanones, pyranones and cyclopentenones. Joao showed that depending on precise reaction conditions it is possible to access a very wide range of 2,4-disubstituted cyclopentenones using very practical synthetic techniques.

It was also gratifying to see the continue progress on our “clean” hydroacylation technology originally published in Nature Chemistry in 2010. This is a remarkable reaction in which we promote the coupling of an aldehyde with an unsaturated system – with no metals or other reagents – simply air!  In the most recent paper Vijay, the pioneer of this area – published a full account of thework, including application of the products to the synthesis of gamma-keto-sulfonamides, sultams, sultones, cyclic N-sulfonyl imines and amides.

So its been a busy and productive year and already 2014 looks set to be as busy. We already have 5 publications for 2014 with one more submitted. As ever its been a privilege to work with my talented and inspiring research group, and I am very grateful to them for all the hard work – and am looking forward to a great 2014.