ao0c00130_si_001.pdf (4.58 MB)
Synthesis of Stable Cholesteryl–Polyethylene Glycol–Peptide Conjugates with Non-Disperse Polyethylene Glycol Lengths
journal contribution
posted on 2020-03-06, 09:30 authored by Edgar Cristóbal-Lecina, Daniel Pulido, Pau Martin-Malpartida, Maria J. Macias, Fernando Albericio, Miriam RoyoA method for conjugating cholesterol
to peptide ligands through
non-disperse polyethylene glycol (ND-PEG) through a non-hydrolysable
linkage is described. The iterative addition of tetraethylene glycol
macrocyclic sulfate to cholesterol (Chol) renders a family of highly
pure well-defined Chol-PEG compounds with different PEG lengths from
4 up to 20 ethylene oxide units, stably linked through an ether bond.
The conjugation of these Chol-PEG compounds to the cyclic (RGDfK)
peptide though Lys5 side chains generates different lengths of Chol-PEG-RGD
conjugates that retain the oligomer purity of the precursors, as analysis
by HRMS and NMR has shown. Other derivatives were synthesized with
similar results, such as Chol-PEG-OCH3 and Chol-PEG conjugated
to glutathione and Tf1 peptides through maleimide–thiol chemoselective
ligation. This method allows the systematic synthesis of highly pure
uniform stable Chol-PEGs, circumventing the use of activation groups
on each elongation step and thus reducing the number of synthesis
steps.