Polyethylene Glycol Conjugation to Amyloidogenic Peptide via Click Reaction

Recently, we have investigated the aggregation and cytotoxicity of short amyloid-like peptides with general form [RF]n (n = 1-5).1 The sequences selected have been shown to be critical in fibrillization. We will also investigate the self-assembly of copolymers of the peptide with poly(ethylene glycol), PEG. PEG is a water soluble polymer that has been approved for pharmaceutical applications. The PEG will be attached to peptide fragments designed to bind to the full disease-causing peptide. We expect it will provide steric stability to peptide fibrils, forming a coating layer that prevents aggregation into larger aggregates as observed as a symptom of amyloid disease. The present work aims at the synthesis of the 2 copolymer using the click reaction as a key step. Click reaction is an interesting synthetic strategy to formation of a stereospecific triazole ring. To obtain the intermediates, 3 was dried in a vacuum oven and then monotosilated in the presence of triethylamine (TEA) in 81% yield (Scheme 1). The Tosyl-hydroxyl-PEG (PEGOTs) were used in the reaction with NaN3 leading to formation of 4 (46%). In parallel, the amino group in side chain of lysine was deprotected and used in conjugation reaction with the activated propyolic acid, leading to 6 (33%). The reaction between 4 and 6 was performed in the presence of t-butanol, CuSO4 and ascorbic acid, obtaining copolymer 2 (37%). Currently, steps c, d and e are being optimized concomitantly with the coupling between 2 and 1, for the formation of 7.