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Sequence-defined Multifunctional Polyethers


By Joshua Walker

For several decades, polyethers, such as polyethylene glycol (PEG) have garnered tremendous interest as functional biomaterials due to their biocompatible nature. Despite this sustained interest, by and large, functionalized derivatives of PEG remain limited to simple terminal modifications or branched core structures. These approaches limit the valency and the degree of functionality accessible to modified PEGs. An iterative synthetic approach holds the potential to overcome these limitations [1].

In a recent article in Nature Chemistry, Livingston and co-workers demonstrated a new, iterative method to synthesize sequence-defined polyethers [2]. In this context, sequence-defined refers to absolute control of both the sequence and dispersity of the polymer of interest. Their approach utilized liquid-phase coupling in combination with size-selective molecular sieving. As others before them, the authors pursued liquid-phase coupling to access fast reaction kinetics and direct reaction monitoring. A key innovation presented in this work was the use of molecular sieving to separate coupled product from excess reagents. Impressively, the authors were able to achieve product recoveries of greater than 94% for each synthetic step. Moreover, product recovery improved as the polyether chain was elongated. Through this work, Livingston and co-workers were able to complete a 6-cycle synthesis for two sequence-defined polyethers at a scale greater than 100 mg. These polyethers were comprised of functional handles (e.g., thiol and azide) that can be further derivatized to incorporate therapeutic payloads, dyes, or targeting ligands. Further, hydrophilic hydroxy and hydrophobic octyl side-arms were incorporated that could be used to alter physical properties of the polyether chain.

The work described here represents the first entrant into the field of sequence-defined PEG-based biomaterials. However, there remain several unanswered questions. Namely, can this synthesis methodology be enriched by incorporating additional functional side chains? Is size-selective molecular sieving generalizable as a method to purify other synthetic sequence-defined materials? In the coming years, it will be interesting to monitor the development of this area as new applications arise in sequence-defined biomaterials.

  1. Sorkin, M. R., Walker, J. A., Brown, J. S. & Alabi, C. A. Versatile Platform for the Synthesis of Orthogonally Cleavable Heteromultifunctional Cross-Linkers. Bioconjugate Chemistry 28, 907–912 (2017). doi:10.1021/acs.bioconjchem.7b00033
  2. Dong, R. et al. Sequence-defined multifunctional polyethers via liquid-phase synthesis with molecular sieving. Nat Chem (2018). doi:10.1038/s41557-018-0169-6