TY - JOUR
T1 - Constraining and Modifying Peptides Using Pd-Mediated Cysteine Allylation
AU - Kriegesmann, Julia
AU - Schlatzer, Thomas
AU - Che, Kateryna
AU - Altdorf, Claudia
AU - Huhmann, Susanne
AU - Kählig, Hanspeter
AU - Kurzbach, Dennis
AU - Breinbauer, Rolf
AU - Becker, Christian F.W.
N1 - Publisher Copyright:
© 2023 The Authors. ChemBioChem published by Wiley-VCH GmbH.
PY - 2023/7/3
Y1 - 2023/7/3
N2 - Over the past decades, several strategies for inducing and stabilizing secondary structure formation in peptides have been developed to increase their proteolytic stability and their binding affinity to specific interaction partners. Here, we report how our recently introduced chemoselective Pd-catalyzed cysteine allylation reaction can be extended to stapling and how the resulting alkene-containing staples themselves can be further modified to introduce additional probes into such stabilized peptides. The latter is demonstrated by introducing a fluorophore as well as a PEG moiety into different stapled peptides using bioorthogonal thiol-ene and Diels-Alder reactions. Furthermore, we investigated structural implications of our allyl staples when used to replace conformationally relevant disulfide bridges. To this end, we chose a selective binder of integrin α3β1 (LXY3), which is only active in its cyclic disulfide form. We replaced the disulfide bridge by different stapling reagents in order to increase stability and binding affinity towards integrin α3β1.
AB - Over the past decades, several strategies for inducing and stabilizing secondary structure formation in peptides have been developed to increase their proteolytic stability and their binding affinity to specific interaction partners. Here, we report how our recently introduced chemoselective Pd-catalyzed cysteine allylation reaction can be extended to stapling and how the resulting alkene-containing staples themselves can be further modified to introduce additional probes into such stabilized peptides. The latter is demonstrated by introducing a fluorophore as well as a PEG moiety into different stapled peptides using bioorthogonal thiol-ene and Diels-Alder reactions. Furthermore, we investigated structural implications of our allyl staples when used to replace conformationally relevant disulfide bridges. To this end, we chose a selective binder of integrin α3β1 (LXY3), which is only active in its cyclic disulfide form. We replaced the disulfide bridge by different stapling reagents in order to increase stability and binding affinity towards integrin α3β1.
KW - allylation reaction
KW - Diels-Alder reaction
KW - peptide stapling
KW - secondary peptide modification
UR - http://www.scopus.com/inward/record.url?scp=85156160997&partnerID=8YFLogxK
U2 - 10.1002/cbic.202300098
DO - 10.1002/cbic.202300098
M3 - Article
C2 - 36917494
AN - SCOPUS:85156160997
VL - 24
JO - ChemBioChem: a european journal of chemical biology
JF - ChemBioChem: a european journal of chemical biology
SN - 1439-4227
IS - 13
M1 - e202300098
ER -