Influence of Sulfur‐Containing Diamino Acid Structure on Covalently Crosslinked Copolypeptide Hydrogels

Abstract

Biologically occurring non‐canonical di‐α‐amino acids were converted into new di‐N‐carboxyanhydride (di‐NCA) monomers in reasonable yields with high purity. Five different di‐NCAs were separately copolymerized with tert‐butyl‐l‐glutamate NCA to obtain covalently crosslinked copolypeptides capable of forming hydrogels with varying crosslinker density. Comparison of hydrogel properties with residue structure revealed that different di‐α‐amino acids were not equivalent in crosslink formation. Notably, l‐cystine was found to produce significantly weaker hydrogels compared to l‐homocystine, l‐cystathionine, and l‐lanthionine, suggesting that l‐cystine may be a sub‐optimal choice of di‐α‐amino acid for preparation of copolypeptide networks. The di‐α‐amino acid crosslinkers also provided different chemical stability, where disulfide crosslinks were readily degraded by reduction, and thioether crosslinks were stable against reduction. This difference in response may provide a means to fine tune the reduction sensitivity of polypeptide biomaterial networks.

Rational construction of polycystine-based nanoparticles for biomedical applications

“…A strongly basic KOtBu initiator was also used to polymerize multiple di- N -carboxyanhydrides (di-NCAs) to prepare high molecular weight copolymers (Scheme 2(B)). 24 Apart from the above traditional initiator, hydroxyl-bearing PEG was applied in the ROP of Cys 2 NCA. 25 The reaction mixture was heated to 45 °C to accelerate the polymerization due to the relatively low reactivity of hydroxyl group.…”

“…Notably, most of the polymerizations of Cys 2 NCA were usually incomplete, with conversion rates of around 70% to 80%, resulting from the formed networks that hindered the reaction between Cys 2 NCA and the embedded polymer chain end. 24 In a recent study reported by Deming's group, the monomer consumption and yield were evaluated in the copolymerization of different di-NCA monomers with Glu NCA using KOtBu as an initiator. 24 The yield could reach more than 90% when the molar percentage of di-NCA was lower than 5%.…”

“…24 In a recent study reported by Deming's group, the monomer consumption and yield were evaluated in the copolymerization of different di-NCA monomers with Glu NCA using KOtBu as an initiator. 24 The yield could reach more than 90% when the molar percentage of di-NCA was lower than 5%. However, the monomer consumption and yield decreased with the increasing molar percentage of di-NCA.…”

Recent Advances and Future Perspectives of Synthetic Polypeptides from N-Carboxyanhydrides

“…Compared with a batch reaction, the microflow strategy enabled the rapid preparation of various NCAs at room temperature. Different than the preparation of NCAs with acid labile-side chains in a batch reactor, which requires acid scavengers (e.g., α-pinene and triethylamine (TEA)) to remove acidic byproducts generated during NCA synthesis, − the NCA synthesis in a microflow reactor employed a flash dilution step to protect the NCAs from being overexposed in an acidic environment, making it a facile and efficient method for the preparation of NCAs with acid-labile side chains (Figure b).…”

Gelating polypeptide matrices based on the difunctional N‐carboxyanhydride diaminopimelic acid cross‐linker

“…Cystine, the endogenous dimerized version of oxidized cysteine, is the only difunctional amino acid found in ribosomal‐derived proteins. Therefore, in polypeptide synthesis, it represents the most common difunctional amino acid feedstock that has been used in carboxyanhydride (NCA) preparation and synthesis . In particular, cystine NCA has been used in the development of a series of multifunctional polypeptides known as core‐crosslinked stars (CCS) or nanogels, which can be successfully designed using this crosslinker in the arm‐first method .…”