Chemical modification of proteins has been responsible for the paradigm shift in the pharmaceutical industry such as the advent of antibody drug conjugate (ADC) therapy. Early strategies focussed on the modification of natural amino acids however, selectivity issues have forced the development of introducing unnatural moieties to act as unique reactive handles for modification. The incorporation of unique functionalities gives the target protein this reactive handle. Aldehyde moieties are not commonly found in nature and thus present themselves as suitable candidates to be incorporated into proteins, fabricating a non-canonical reactive handle. This aldehyde handle allows for site specific and site selective conjugation without modifying other residues or perturbing overall protein structure. The ability to site selectively modify proteins bearing installed aldehyde handles is re-writing approaches to the construction of covalently linked, homogenous protein constructs. Herein we present an NHC-catalysed cross-acyloin like ligation for the site-selective modification of proteins. This novel strategy utilises Umpolung chemistry to construct a stable C-C bond between a protein aldehyde and a small molecule aldehyde under physiological conditions. This aldehyde-aldehyde coupling is achieved through the formation of a key enamine analogue intermediate, commonly referred to as the ‘Breslow Intermediate’.

Site-selective chemical protein modification <i>via</i> Umpolung catalysis

2019 Spring National Meeting

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Site-selective chemical protein modification via Umpolung catalysis