蛋白质-聚氨基酸偶联物的高效合成与应用

张冲; 吕华

doi:10.11777/j.issn1000-3304.2018.17204

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蛋白质-聚氨基酸偶联物的高效合成与应用

专论 | 更新时间：2021-01-26

- 蛋白质-聚氨基酸偶联物的高效合成与应用
- Efficient Synthesis and Application of Protein-Poly(α-amino acid) Conjugates
- 高分子学报 2018年第1期页码：21-31
- 作者机构：
  
  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
- 作者简介：
  
  [ "吕华, 男, 1983年出生.2006年于北京大学获学士学位, 2011年于美国伊利诺伊大学香槟分校获博士学位, 2011~2014年在美国斯克里普斯研究所从事博士后研究.2014年任北京大学化学与分子工程学院研究员, 博士生导师.2015年度获得中组部青年千人计划支持(第十一批)资助.研究方向包括可控开环聚合、聚氨基酸生物材料和蛋白质偶联物" ]
- 基金信息：
  
  国家自然科学基金(21474004);国家自然科学基金(21434008)
- DOI：10.11777/j.issn1000-3304.2018.17204
  中图分类号：
- 纸质出版日期：2018-1-20，
  
  收稿日期：2017-7-28，
  
  修回日期：2017-9-22，
扫描看全文
张冲, 吕华. 蛋白质-聚氨基酸偶联物的高效合成与应用[J]. 高分子学报, 2018,(1):21-31.

Zhang Chong, Lu Hua. Efficient Synthesis and Application of Protein-Poly(α-amino acid) Conjugates[J]. Acta Polymerica Sinica, 2018,(1):21-31.
张冲, 吕华. 蛋白质-聚氨基酸偶联物的高效合成与应用[J]. 高分子学报, 2018,(1):21-31. DOI： 10.11777/j.issn1000-3304.2018.17204.

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.

摘要

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

-氨基酸-

-羧基酸酐（

-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.

Abstract

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(

-amino acid)s (P

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

AAs conjugates. Specifically

we discuss our developments in: (1) Recent developments in the controlled ring-opening polymerization (ROP) of

-amino acid

-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

AAs for site-specific protein conjugation

and construction of various topological structures. Using PhSTMS initiator

in situ

generates a reactive phenyl thioester group at one end of the P

AAs

which can be used for protein

-terminus conjugation

via

native chemical ligation (NCL); moreover

ROP of glycine NCA yields oligoglycine at the other end of P

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

AA conjugates including the head-to-tail circular conjugates. (3) Development of functional P

AAs for potential protein conjugation. Various functional P

AAs have been developed as delivery materials or hydrogels. To further expand the arsenal of P

AAs for potential modulation of protein functions

AAs that mimic protein post-translational modifications (PTM) are synthesized; On the other hand

a series of multiple stimuli-responsive P

AAs are also produced. These P

AAs show interesting enzyme

light

and/or thermal responsiveness

which could be potentially harnessed for modulation of protein functions in the future.

关键词

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

Keywords

Protein conjugationPoly(α-amino acid)PTM mimickingTopologyStimuli-responsiveness

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