TY - JOUR
T1 - Site-selective C-C modification of proteins at neutral pH using organocatalyst-mediated cross aldol ligations
AU - Spears, Richard James
AU - Brabham, Robin Louis
AU - Budhadev, Darshita
AU - Keenan, Tessa
AU - McKenna, Sophie Elizabeth
AU - Walton, Julia
AU - Brannigan, James Antony
AU - Brzozowski, Andrzej Marek
AU - Wilkinson, Anthony Joseph
AU - Plevin, Michael John
AU - Fascione, Martin Anthony
N1 - © The Royal Society of Chemistry 2018
PY - 2018/7/7
Y1 - 2018/7/7
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85049299619&partnerID=8YFLogxK
U2 - 10.1039/C8SC01617H
DO - 10.1039/C8SC01617H
M3 - Article
SN - 2041-6520
VL - 9
SP - 5585
EP - 5593
JO - Chemical Science
JF - Chemical Science
IS - 25
ER -