A powerful strategy for selectively modifying the side-chains of proteins has been developed, which is hoped will enable the creation of new tools to investigate protein interactions involved in human diseases.

Modifying the side-chains of the amino acids that make up proteins is simple, but because a particular type of side-chain may appear many times in a given protein, modifying just one of them is a tough challenge. Brian Popp and Zachary Ball at Rice University, Houston, have been using chemical reactivity ideas and reaction design to try and solve this problem.

In their solution, they decided to dispense with the standard approach of designing a highly selective reagent. Instead, they used a reagent that is hardly selective at all, but one that only works in the presence of a rhodium catalyst. The trick is to place the catalyst exactly where it’s needed by attaching it to a coiled peptide that binds to the right bit of the target protein. This brings the catalyst and the side-chain into close proximity, allowing them to react as soon as the reagent – a diazo derivative of styrene ­– is added.

Ball thinks that this approach is ‘a big step forward’. The main benefit is that the high reactivity of the diazo compound allows it to react with the side-chains of over half the naturally occurring amino acids, a broader range than any established method. The method is also highly specific, as any catalytic units that start to react where they are not wanted are quickly destroyed by reaction with water, which is the solvent for the reaction.

As well as looking to establish the robustness of their new method, future work may involve investigating how it could be used to tag, image, or modify the structure or function of natural proteins. “We believe this work will create powerful tools to investigate transient protein interactions, such as those along signalling pathways that lead to human disease,” says Ball.

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