RT Journal Article
SR Electronic
T1 Solid Phase Synthesis of Fluorosulfate Containing Macrocycles for Chemoproteomic Workflows
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2023.02.17.529022
DO 10.1101/2023.02.17.529022
A1 Faucher, Franco F.
A1 Abegg, Daniel
A1 Ipock, Phillip
A1 Adibekian, Alexander
A1 Lovell, Scott
A1 Bogyo, Matthew
YR 2023
UL http://biorxiv.org/content/early/2023/02/18/2023.02.17.529022.abstract
AB Macrocyclic peptides are attractive for chemoproteomic applications due to their modular synthesis and potential for high target selectivity. We describe a solid phase synthesis method for the efficient generation of libraries of small macrocycles that contain an electrophile and alkyne handle. The modular synthesis produces libraries that can be directly screened using simple SDS-PAGE readouts and then optimal lead molecules applied to proteomic analysis. We generated a library of 480 macrocyclic peptides containing the weakly reactive fluorosulfate (OSF) electrophile. Initial screening of a subset of the library containing each of the various diversity elements identified initial molecules of interest. The corresponding positional and confirmational isomers were then screened to select molecules that showed specific protein labeling patterns that were dependent on the probe structure. The most promising hits were applied to standard chemoproteomic workflows to identify protein targets. Our results demonstrate the feasibility of rapid, on-resin synthesis of diverse macrocyclic electrophiles to generate new classes of covalent ligands.Competing Interest StatementThe authors have declared no competing interest.