The recent advances in accelerated polymerization of
Open-air synthesis of oligo(ethylene glycol)-functionalized polypeptides from non-purified N -carboxyanhydrides
With PEG-like properties, such as hydrophilicity and stealth effect against protein absorption, oligo(ethylene glycol) (OEG)-functionalized polypeptides have emerged as a new class of biomaterials alternative to PEG with polypeptide-like properties. Synthesis of this class of materials, however, has been demonstrated very challenging, as the synthesis and purification of OEG-functionalized N -carboxyanhydrides (OEG-NCAs) in high purity, which is critical for the success in polymerization, is tedious and often results in low yield. OEG-functionalized polypeptides are therefore only accessible to a few limited labs with expertise in this specialized NCA chemistry and materials. Here, we report the controlled synthesis of OEG-functionalized polypeptides in high yield directly from the OEG-functionalized amino acids via easy and reproducible polymerization of non-purified OEG-NCAs. The prepared amphiphilic block copolypeptides can self-assemble into narrowly dispersed nanoparticles in water, which show properties suitable for drug delivery applications.
- Award ID(s):
- 1905097
- Publication Date:
- NSF-PAR ID:
- 10233138
- Journal Name:
- Biomaterials Science
- ISSN:
- 2047-4830
- Sponsoring Org:
- National Science Foundation
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Abstract N -carboxyanhydrides (NCAs) enriched the toolbox to prepare well-defined polypeptide materials. Herein we report the use of crown ether (CE) to catalyze the polymerization of NCA initiated by conventional primary amine initiators in solvents with low polarity and low hydrogen-bonding ability. The cyclic structure of the CE played a crucial role in the catalysis, with 18-crown-6 enabling the fastest polymerization kinetics. The fast polymerization kinetics outpaced common side reactions, enabling the preparation of well-defined polypeptides using an α-helical macroinitiator. Experimental results as well as the simulation methods suggested that CE changed the binding geometry between NCA and propagating amino chain-end, which promoted the molecular interactions and lowered the activation energy for ring-opening reactions of NCAs. This work not only provides an efficient strategy to prepare well-defined polypeptides with functionalized C-termini, but also guides the design of catalysts for NCA polymerization. -
Ribozymes synthesize proteins in a highly regulated local environment to minimize side reactions caused by various competing species. In contrast, it is challenging to prepare synthetic polypeptides from the polymerization of N -carboxyanhydrides (NCAs) in the presence of water and impurities, which induce monomer degradations and chain terminations, respectively. Inspired by natural protein synthesis, we herein report the preparation of well-defined polypeptides in the presence of competing species, by using a water/dichloromethane biphasic system with macroinitiators anchored at the interface. The impurities are extracted into the aqueous phase in situ, and the localized macroinitiators allow for NCA polymerization at a rate which outpaces water-induced side reactions. Our polymerization strategy streamlines the process from amino acids toward high molecular weight polypeptides with low dispersity by circumventing the tedious NCA purification and the demands for air-free conditions, enabling low-cost, large-scale production of polypeptides that has potential to change the paradigm of polypeptide-based biomaterials.
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The polymerization of N -carboxyanhydrides (NCAs) affords access to a vast array of synthetic polypeptides with tunable molecular weights, functionalities, and architectures. The use of light to achieve spatiotemporal control over these polymerizations could expand their applicability to a variety of areas, including 3D printing and photolithography. In this report we utilized 2-(2-nitrophenyl)propyloxycarbonyl (NPPOC) as a photoprotecting group to cage a primary amine initiator that is activated upon UV irradiation. NPPOC photocages underwent quantitative deprotection and afforded better polymerization control compared to previously reported photocaged amines for NCA polymerizations. Furthermore, the addition of a small equivalence of base enhanced the control and resulted in polymers with lower dispersities. Overall, this method advances photo-controlled polypeptide synthesis by demonstrating high chain-end fidelity, efficient chain extension, and the ability to synthesize block copolymers.
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Accepted Manuscript1.0
- Publisher's Version of Record
- https://doi.org/10.1039/d1bm00223f
