Embedding Peptides into Synthetic Polymers: Radical Ring-Opening Copolymerization of Cyclic Peptides

Abstract

Biopolymers such as proteins and nucleic acids are the key building blocks of life. Synthetic polymers have nevertheless revolutionized our everyday life through their robust synthetic accessibility. Combining the unmatched functionality of biopolymers with the robustness of tailorable synthetic polymers holds the promise to create materials that can be designed ad hoc for a wide array of applications. Radical polymerization is the most widely applied polymerization technique in both fundamental science and industrial polymer production. While this polymerization technique is robust and well controlled, it generally yields unfunctional all-carbon backbones. Combinations of natural polymers such as peptides, with synthetic polymers, are thus limited to tethering peptides onto the side chains or chain ends of the latter. This synthetic limitation is a critical restraint, considering that the function of biopolymers is programmed into the sequence of their main chain (i.e., primary structure). Here, we report the radical copolymerization of peptides and synthetic comonomers yielding synthetic polymers with defined peptide sequences embedded into their main chain. Key was the development of a solid-phase peptide synthesis (SPPS) approach to generate synthetic access to peptide conjugates containing allylic sulfides. Following cyclization, the obtained peptide monomers can be readily copolymerized with N,N-dimethylacrylamide (DMA)�controlled by reversible addition−fragmentation chain transfer (RAFT). Importantly, the developed synthetic strategy is compatible with all 20 standard amino acids and uses exclusively standard SPPS chemicals or chemicals accessible in one-step synthesis�prerequisite for widespread and universal application.

Efficient Synthesis of Hydrolytically Degradable Block Copolymer Nanoparticles via Reverse Sequence Polymerization‐Induced Self‐Assembly in Aqueous Media

“…Recently, various research groups have reported the statistical copolymerization of cyclic monomers with vinyl monomers to produce hydrolytically degradable copolymer backbones [19,20,21,22,26,29–31,34,37,38] . In principle, this approach could form part of the solution to the global challenge of plastic waste [39,40] .…”

Efficient Synthesis of Hydrolytically Degradable Block Copolymer Nanoparticles via Reverse Sequence Polymerization‐Induced Self‐Assembly in Aqueous Media

“…Recently, various research groups have reported the statistical copolymerization of cyclic monomers with vinyl monomers to produce hydrolytically degradable copolymer backbones [19,20,21,22,26,29–31,34,37,38] . In principle, this approach could form part of the solution to the global challenge of plastic waste [39,40] .…”

Controlled Ring-Opening Polymerization of Macrocyclic Monomers Based on Ring-Opening/Ring-Closing Cascade Reaction

“…In theory, the controlled ROP of macrocyclic monomers can be achieved by combining rapid and simultaneous initiation reactions. To date, controlled ring-opening metathesis polymerization (ROMP) − and controlled radical ROP − of macrocyclic monomers with living polymerization characteristics have been developed based on this strategy and applied in the synthesis of polymers with controlled molecular weights and relatively narrow dispersities ( Đ ≤ 1.4). Specifically, sequence-controlled polymers have been synthesized by controlled ROMP using a 1,6-enyne metathesis cascade motif, ,− cis -olefin, − or a strained 3-substituted cyclooctene as the ring-opening trigger.…”

“…Specifically, sequence-controlled polymers have been synthesized by controlled ROMP using a 1,6-enyne metathesis cascade motif, ,− cis -olefin, − or a strained 3-substituted cyclooctene as the ring-opening trigger. Backbone-functionalized polymers have been synthesized from macrocycles containing an allylic sulfone radical cascade moiety by controlled radical ROP assisted with reversible addition–fragmentation chain transfer polymerization technique. − Although these metathesis and radical cascade reactions facilitate controlled ROP of macrocyclic monomers, the trigger moieties used are all incorporated into the resultant polymer chains. − ,− This inevitably produces unnecessary bulky auxiliary groups on the backbones of the obtained polymers.…”

“…To enhance the driving force for ROP of macrocyclic monomers, an ingenious approach is to introduce a “ring-opening trigger” into the macrocyclic monomer ring. − By selectively reacting it with the active chain end group, side reactions can be effectively suppressed during polymerization. In theory, the controlled ROP of macrocyclic monomers can be achieved by combining rapid and simultaneous initiation reactions.…”