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北京分子科学国家实验室 高分子化学与物理教育部重点实验室 软物质科学与工程中心 北京大学化学与分子工程学院 北京 100871
Published:20 January 2018,
Received:28 July 2017,
Revised:22 September 2017,
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Zhang Chong, Lu Hua. Efficient Synthesis and Application of Protein-Poly(
Zhang Chong, Lu Hua. Efficient Synthesis and Application of Protein-Poly(
蛋白质-高分子偶联物是重要的临床药物,可用于多种疾病的治疗.寻找新的生物可降解高分子材料来替代传统的聚乙二醇和发展高效、位点特异性的偶联方法是该领域目前所面临的2个重要挑战.聚氨基酸是一类具有较好生物相容性、可生物降解、含有丰富侧链官能团的仿生功能高分子,在蛋白质修饰方面具有突出的优势,是有较大潜力的聚乙二醇替代物.本专论主要从新型
α
-氨基酸-
N
-羧基酸酐(
N
-carboxyanhydrides,NCA)可控开环聚合方法、聚氨基酸原位官能化制备位点特异性蛋白质偶联物、扩展功能聚氨基酸分子库调控蛋白质功能等3个方面详细介绍蛋白质-聚氨基酸领域的研究进展,并对这类新型偶联物的发展进行了简单的评述和展望.
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 (P
α
AAs) 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-P
α
AAs 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 P
α
AAs 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 P
α
AAs
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 P
α
AAs
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-P
α
AA conjugates including the head-to-tail circular conjugates. (3) Development of functional P
α
AAs for potential protein conjugation. Various functional P
α
AAs have been developed as delivery materials or hydrogels. To further expand the arsenal of P
α
AAs for potential modulation of protein functions
P
α
AAs that mimic protein post-translational modifications (PTM) are synthesized; On the other hand
a series of multiple stimuli-responsive P
α
AAs are also produced. These P
α
AAs show interesting enzyme
light
and/or thermal responsiveness
which could be potentially harnessed for modulation of protein functions in the future.
蛋白质偶联物聚氨基酸模拟蛋白翻译后修饰拓扑结构刺激响应性
Protein conjugationPoly(α-amino acid)PTM mimickingTopologyStimuli-responsiveness
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