Issue 25, 2018

Site-selective C–C modification of proteins at neutral pH using organocatalyst-mediated cross aldol ligations

Abstract

The bioconjugation of proteins with small molecules has proved an invaluable strategy for probing and perturbing biological mechanisms. The general use of chemical methods for protein functionalisation can be limited however by the requirement for complicated reaction partners to be present in large excess, and harsh conditions which are incompatible with many protein scaffolds. Herein we describe a site-selective organocatalyst-mediated protein aldol ligation (OPAL) that affords stable carbon–carbon linked bioconjugates at neutral pH. OPAL enables rapid modification of proteins using simple aldehyde probes in minimal excess, and is utilised here in the affinity tagging of proteins in cell lysate. Furthermore we demonstrate that the β-hydroxy aldehyde OPAL product can be functionalised again at neutral pH in a tandem organocatalyst-mediated oxime ligation. This tandem strategy is showcased in the ‘chemical mimicry’ of a previously inaccessible natural dual post-translationally modified protein integral to the pathogenesis of the neglected tropical disease Leishmaniasis.

Graphical abstract: Site-selective C–C modification of proteins at neutral pH using organocatalyst-mediated cross aldol ligations

Supplementary files

Article information

Article type
Edge Article
Submitted
09 apr 2018
Accepted
31 may 2018
First published
31 may 2018
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2018,9, 5585-5593

Site-selective C–C modification of proteins at neutral pH using organocatalyst-mediated cross aldol ligations

R. J. Spears, R. L. Brabham, D. Budhadev, T. Keenan, S. McKenna, J. Walton, James. A. Brannigan, A. M. Brzozowski, A. J. Wilkinson, M. Plevin and M. A. Fascione, Chem. Sci., 2018, 9, 5585 DOI: 10.1039/C8SC01617H

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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