Citation: Zhang Chong, Lu Hua. Efficient Synthesis and Application of Protein-Poly(α-amino acid) Conjugates[J]. Acta Polymerica Sinica, ;2018, (1): 21-31. doi: 10.11777/j.issn1000-3304.2018.17204 shu

Efficient Synthesis and Application of Protein-Poly(α-amino acid) Conjugates

Zhang Chong ,
Lu Hua ^,

Beijing National Laboratory for Molecular Sciences, Key Laboratory of Polymer Chemistry and Physics of Ministry of Education, Center for Soft Matter Science and Engineering, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871

Corresponding author: Lu Hua, chemhualu@pku.edu.cn
Received Date: 28 July 2017
Revised Date: 22 September 2017

Protein-polymer conjugates are important therapeutics for various diseases. There are currently two major challenges in this field: one is the search of new biodegradable polymers beyond traditional PEGylation, and the other is to develop highly efficient and site-specific conjugation strategy. Poly(α-amino acid)s (PαAAs) are biodegradable and biocompatible polymers with tunable properties and numerous functions, making them promising candidates for protein modification. In this review, we summarize our recent progresses in protein-PαAAs conjugates. Specifically, we discuss our developments in: (1) Recent developments in the controlled ring-opening polymerization (ROP) of α-amino acid N-carboxyanhydrides (NCAs), including amine-based initiators, organometallic initiators, organosilicon amines initiators and sulfide-based initiators. For instance, trimethylsilyl phenylsulfide (PhSTMS) is a novel initiator for controlled ROP of NCAs. It exhibits higher nucleophilicity than conventional amine-based initiator, and thus affords considerably higher chain initiation rate to ensure a more controlled polymerization. Moreover, this initiator is well-tolerated to various functional groups. (2) In situ functionalization of PαAAs for site-specific protein conjugation, and construction of various topological structures. Using PhSTMS initiator, it in situ generates a reactive phenyl thioester group at one end of the PαAAs, which can be used for protein N-terminus conjugation via native chemical ligation (NCL); moreover, ROP of glycine NCA yields oligoglycine at the other end of PαAAs, which can be used for C-terminus protein conjugation via sortase-A mediated ligation (SML). More interestingly, combinatory use of the two methods can construct various topological protein-PαAA conjugates including the head-to-tail circular conjugates. (3) Development of functional PαAAs for potential protein conjugation. Various functional PαAAs have been developed as delivery materials or hydrogels. To further expand the arsenal of PαAAs for potential modulation of protein functions, PαAAs that mimic protein post-translational modifications (PTM) are synthesized; On the other hand, a series of multiple stimuli-responsive PαAAs are also produced. These PαAAs show interesting enzyme, light, and/or thermal responsiveness, which could be potentially harnessed for modulation of protein functions in the future.
- Protein conjugation,
- Poly(α-amino acid),
- PTM mimicking,
- Topology,
- Stimuli-responsiveness
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