One‐Pot Synthesis of Thermoresponsive Amyloidogenic Peptide–Polymer Conjugates via Thio–Bromo “Click” Reaction of RAFT Polymers

Abstract

A synthetic strategy to efficiently prepare main-chain peptide-polymer conjugates probing their aggregation in solution is described. An in situ tandem reaction based on aminolysis/thio-bromo "click" reaction is performed to tether an amyloidogenic peptide fragment amyloid-β (Leu-Val-Phe-Phe (LVFF)) to the ω-chain end of poly(diethylene glycol methyl ether acrylate) (PDEGA), prepared via reversible addition fragmentation chain transfer polymerization. Structural confirmation of the constructed conjugates PDEGA-LVFF (M = 5600, Ð = 1.21), (M = 7600, Ð = 1.16), and (M = 8900, Ð = 1.15) is successfully made by combined studies of H NMR, size-exclusion chromatography, matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry, and electrospray ionization time-of-flight (ESI-TOF) mass spectrometry. The effect of the peptidic constituent on the thermoresponsive behavior of the polymer is examined by UV-vis spectroscopy, and the self-assembly behavior of the amphiphilic conjugate is further exploited, exhibiting micellar morphology in aqueous solution.

Thio‐Bromo “Click” Reaction Derived Polymer–Peptide Conjugates for Their Self‐Assembled Fibrillar Nanostructures

“…To prepare the polymer–peptide conjugate, first α‐bromo‐acyl derivatives of the peptides were synthesized via a solution phase peptide synthesis approach. [ 36 ] As a typical example, initially tetrapeptide Boc derivative of FFFF‐OMe was synthesized (Scheme S1, Supporting Information) with the N ‐terminus protected by the Boc‐group and the C ‐terminus protected by the methyl group via classical peptide‐synthesis, followed by methylester deprotection, where all the intermediate compounds were fully characterized (Figures S1–S10, Supporting Information). The complete structural confirmation of the synthesized peptide Boc‐FFFF‐OMe ( 5 ) was made by NMR and ESI‐TOF MS spectroscopy (Figures S11–S13, Supporting Information).…”

Bifunctional Peptide–Polymer Conjugate-Based Fibers via a One-Pot Tandem Disulfide Reduction Coupled to a Thio-Bromo “Click” Reaction

“…Electrospray ionization time-of-flight mass spectroscopy (ESI-TOF MS) spectra for polymer 3 further confirmed the molecular structure by illustrating the appearance of peaks with two different series of 1 + and 2 + charged states, where the observed peaks (e.g., the isotopic peak maxima at m / z = 1565.9513 g mol –1 for [M + Na] + with n = 30, and at m / z = 860.5184 g mol –1 for [M + 2Na] 2+ with n = 33, respectively), match with the simulated isotopic patterns of the proposed ions ( Figure S12 , Supporting Information). 47 …”

Polymerizations by RAFT: Developments of the Technique and Its Application in the Synthesis of Tailored (Co)polymers

“…They also prepared physically cross‐linked hydrogels with tuneable stiffness due to the presence of the LVFF peptide sequence. [ 221,222 ] Similarly Thang and co‐workers modified the R group of a RAFT agent with a peptide sequence of ten, known as the cell‐penetrating peptides. This modified CTA was able to control the synthesis of well‐defined block copolymers (PEG and butyl acrylate) forming rods and vesicles in water.…”