A moisture-tolerant route to unprotected α/β-amino acid N-carboxyanhydrides and facile synthesis of hyperbranched polypeptides

Tian, Zhijia; Zhang, Zhengchu; Wang, Shuo; Lu, Hua

doi:10.1038/s41467-021-25689-y

Cited by 79 publications

(64 citation statements)

References 59 publications

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“…Highly pure ProNCA was prepared using a moisture-resistant method that our lab recently developed [ 40 ], which significantly simplified the conventional procedure that involves laborious workup. The application of this method also improved the yield to 72%, up from 30% reported previously.…”

Section: Resultsmentioning

confidence: 99%

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Tian

Xiong

et al. 2022

National Science Review

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The production of polypeptides via the ring-opening polymerization (ROP) of N-carboxyanhydride (NCA) is usually conducted under stringent anhydrous conditions. The ROP of proline NCA (ProNCA) for the synthesis of poly-L-proline (PLP) is particularly challenging due to the premature product precipitation as polyproline type I helices, leading to slow reactions up to one week, poor control of the molar mass, and laborious workup. Here, we report the unexpected water-assisted controlled ROP of ProNCA, which affords well-defined PLP as polyproline II helices in 2-5 minutes and almost quantitative yields. Experimental and theoretical studies together suggest an as-yet-unreported role of water in facilitating proton shift, which significantly lowers the energy barrier of the chain propagation. The scope of initiators can be expanded from hydrophobic amines to also encompass hydrophilic amines and thiol-bearing nucleophiles, including complex biomacromolecules such as proteins. Protein-mediated ROP of ProNCA conveniently affords various protein-PLP conjugates via a grafting-from approach. PLP modification not only preserves the biological activities of the native proteins, but also enhances their resistance to extreme conditions. Moreover, PLP modification extends the elimination half-life of asparaginase (ASNase), a first-line anticancer drug for lymphoma treatment, by 18 folds and mitigates the immunogenicity of wt ASNase by more than 250 folds. Together, this work provides a simple solution to a longstanding problem in PLP synthesis, and offers valuable guidance for the development of water-resistant ROP of other proline-like NCAs. The facile access of PLP can greatly boost the application potential of PLP-based functional materials for engineering industry enzymes and therapeutic proteins.

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Section: Resultsmentioning

confidence: 99%

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Tian

Xiong

et al. 2022

National Science Review

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“…Similarly, in 1964, Saito reported that free β-OH Thr NCA could be formed but polymerization attempts led to rearrangement to the 2-oxazolidinone derivative rather than the polypeptide . Recent work on free β-OH Thr NCA has also shown that epimerization of the α-carbon leads to diastereomers . Therefore, NCA studies have used various β-OH-protected Thrs including trimethylsilyl (TMS), , tert -butyl, benzyl (Bn), and diphenylphosphate as protecting or functional groups.…”

Section: Introductionmentioning

confidence: 99%

Biomimetic Glycosylated Polythreonines by N-Carboxyanhydride Polymerization

Deleray

Kramer

2022

Biomacromolecules

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Glycosylated threonine (Thr) is a structural motif found in seemingly disparate natural proteins from deep-sea collagen to mucins. Synthetic mimics of these important proteins are of great interest in biomedicine. Such materials also provide ready access to probe the contributions of individual amino acids to protein structure in a controlled and tunable manner. N-Carboxyanhydride (NCA) polymerization is one major route to such biomimetic polypeptides. However, challenges in the preparation and polymerization of Thr NCAs have impeded obtaining such structures. Here, we present optimized routes to several glycosylated and acetylated Thr NCAs of high analytical purity. Transition metal catalysis produced tunable homo-, statistical, and block-polypeptides with predictable chain lengths and low dispersities. We conducted structural work to examine their aqueous conformations and found that a high content of free OH Thr induces the formation of water-insoluble β-sheets. However, glycosylation appears to induce a polyproline II-type helical conformation, which sheds light on the role of glyco-Thr in rigid proteins such as mucins and collagen.

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“…Synthetic polypeptides are protein-like polymers having precise control over α-helical and β-sheet conformations for wide range of applications in materials science and biomedical fields. − Polypeptides are synthesized by ring-opening polymerization (ROP) of N -carboxyanhydride (NCA) monomers of l -amino acids by nucleophiles or base initiators, − and in this process, secondary structures of the propagating polypeptide chains are rationalized as being a foremost deciding factor in determining the kinetics and building the high-molecular-weight polymers . α-Helical polypeptides render excellent solubility in the polymerization medium to speed up the ROP process − and exhibit “livingness” to make extended block copolymer architectures .…”

Section: Introductionmentioning

confidence: 99%

Tertiary-Butylbenzene Functionalization as a Strategy for β-Sheet Polypeptides

Nisal

Jayakannan

2022

Biomacromolecules

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β-Sheet forming polypeptides are one of the least explored synthetic systems due to their uncontrolled precipitation in the ring-opening polymerization (ROP) synthetic methodology. Here, a new t-butylbenzene functionalization approach is introduced to overcome this limitation by sterically controlling the propagating polymer chains, and homogeneous polymerization with good control over chain growth was accomplished. New bulky N-carboxyanhydride monomers were designed having t-butylbenzene pendant by multistep organic synthesis, and N-heterocyclic carbene was explored as a catalyst to make high-molecular-weight and narrow polydisperse soluble polypeptides. This ROP process was successfully demonstrated for two β-sheet forming polypeptides such as poly(l-serine) and poly(l-cysteine). These new t-butylbenzene-functionalized polypeptides were found to be readily soluble in tetrahydrofuran, chloroform, and so forth, and they were produced in high molecular weights having M n = 32 kDa with dispersity D̵ ≤ 1.3. ROP kinetics were studied by real-time Fourier transform infrared and 1H NMR to determine the actual content of the secondary structures in the propagating chains. These studies established that the α-helical conformational front in the propagation chain was speeding up the polymerization kinetics with good degree of control in the ROP process. Reversible-conformational transitions in the post-polymerization deprotection were found to restore the β-sheet secondary structures in poly(l-serine)s. The newly developed t-butylbenzene-substituted steric-hindrance approach is valuable in yielding soluble polymers, and this approach could be useful for exploring new polypeptide architectures for long-term impact.

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A moisture-tolerant route to unprotected α/β-amino acid N-carboxyanhydrides and facile synthesis of hyperbranched polypeptides

Cited by 79 publications

References 59 publications

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Water-assisted and protein-initiated fast and controlled ring-opening polymerization of proline N-carboxyanhydride

Biomimetic Glycosylated Polythreonines by N-Carboxyanhydride Polymerization

Tertiary-Butylbenzene Functionalization as a Strategy for β-Sheet Polypeptides

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