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(511c) Clickable Synthetic Polypeptides As a Tranformable Backbones for Biomaterials

Hammond, P. T., Massachusetts Institute of Technology

One of the key challenges in the field of polymer chemistry is the ability to generate macromolecules with the degree of control over composition and diversity of function that nature is able to exhibit with biomacromolecular species. Although it is possible to generate the very specific sequences of naturally occurring polypeptides, these approaches are limited in practice to relatively small quantities and short peptide sequences that can generally only be provided at high cost due to low yields, time consuming process steps and costly purifications.   Synthetic polypeptides introduce a powerful capability to generate macromolecular species using the amino acid backbone found in nature, thus providing a route to biocompatible polymeric systems with programmable function.  A number of exciting developments have occurred with the advent of controlled polymerization of N-carboxyanhydrides (NCA), which has been extended considerably with the introduction of new catalyst systems that enhance control and block distribution.   Although these methods can enable design with a number of naturally occurring amino acids, the NCA process can be restrictive with regard to the functionality of the monomer side group allowed, thus preventing the direct incorporation of various amine, acid, thiol, and other functional sidegroups that dictate polymer function, structure, and responsive behavior to temperature or pH among many other properties.   Steric effects also limit the incorporation of amino acids with large macromolecular side chains. There is a need to create a more readily adaptable platform to attach a broader range of groups at the amino acid backbone with ease and control.  Highly quantitative functionalization chemistries have been developed and evolved for use with polymers over the past several years, such as the Sharpless ‘click’ chemistry involving the near-quantitative reactions of propargyl and azide groups.  

To broaden the range of capabilities possible with the NCA chemistry platform, our research group recently introduced the first NCA polymerized synthetic polypeptides with ‘clickable’ side groups through the introduction of a new NCA polymer, poly(γ-propargyl L-glutamate) (PPLG), which contains a pendant alkyne group that can be reacted with an azide.   We were able to demonstrate key advantages to the use of a clickable backbone system with a nearly quantitative post-polymerization functionalization step, including: a) The ability to directly attach functional groups that are ordinarily difficult due to cross-reaction or the need for exhaustive protection-deprotection strategies that greatly lower yield and impact function, including amines, imines, acids, alchohols, thiols and combinations of polar and nonpolar groups that can exhibit mixed charge or function and b) Unusually high grafting-on density with oligomeric grafts in a range of molecular weights, including up to 99% functionalization with polyethylene glycol (PEG) macromolecules up to 5000 daltonsThis capability provides an opportunity to create new types of graft copolymers that would not be accessible with other methods to generate biomimetic and bioinspired polymers such as artificial proteoglycans and densely grafted polymers with unique swelling, anti-fouling or pH responsive properties.

Ease of synthesis with both small molecular and macromolecular side groups that exhibit a broad range of polarity and charge provides a key platform for the generation of families of synthetic polypeptides that more directly mimic the adaptive function and responsive behavior of naturally occurring polypeptides while introducing the opportunity to incorporate new function.   Examples of the use of this platform from the generation of responsive polymeric micelles that are triggered at key biological pH conditions, and new hydrogel materials, to polymers that can act as native antimicrobial peptides with much lower toxicity will be discussed.