The Synthesis Of Amide Bond-containing Monodisperse Polyethylene Glycols By SPPS

In biopharmaceutical formulation,PEGylation of the biomacromolecules is a commonly used approach to increase solubility and stability,to reduce immunogenicity and dosing frequency,and to optimize pharmacokinetic.PEGs have been the most frequently used polymers in biomedical research and their properties have set the "gold standard" for biomaterials.Although monodisperse polyethylene glycols(M-PEGs)above 4000 Da are especially valuable in biomedical applications,their synthesis remains a long-standing challenge.To this end,a peptide-based strategy for such M-PEGs was developed.With macrocyclic sulfates as the key intermediates,a panel of oligoethylene glycol(OEG)containing omega-amino acids were prepared with high efficiency.To address the difficulties in conjugating high MW fragments with an ether bond,an amide bond,which can be easily constructed under mild conditions with a broad spectrum of methods,was used instead of an ether bond.Through Fmoc-based solid phase peptide synthesis(SPPS),these amino acids could be conveniently assembled into a series of amide bond-containing M-PEGs with high flexibility in molecular weight and amide density selection.With this strategy,M-PEGs of high A/E ratio(1/12)series includes 2580.4 Da,4921.8 Da,7263.1 Da and low A/E ratio(1/24)series includes 3580.0 Da,6921.0 Da,10 262.0 Da were prepared.HPLC and MALDI-TOF mass analysis of these amide bond containing M-PEGs were then carried out.HPLC chromatograms and MALDI-TOF spectra indicated that they are monodisperse.The biocompatibility of M-PEG with an MW of 10 260 Da was assessed in a mice model and no acute toxicity was observed.