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Article(id=1308841060105806434, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840985296204417, articleNumber=null, orderNo=null, doi=10.16438/j.0513-4870.2025-0597, pmid=null, cstr=null, oa=null, hot=null, price=null, onlineType=0, articleFormat=0, articleType=null, articleTypeStr=null, receivedDate=1748188800000, receivedDateStr=2025-05-26, revisedDate=1753545600000, revisedDateStr=2025-07-27, acceptedDate=null, acceptedDateStr=null, onlineDate=1789981625819, onlineDateStr=2026-09-21, pubDate=1778515200000, pubDateStr=2026-05-12, doiRegisterDate=null, doiRegisterDateStr=null, onlineIssueDate=1789981625819, onlineIssueDateStr=2026-09-21, onlineJustAcceptDate=null, onlineJustAcceptDateStr=null, onlineFirstDate=null, onlineFirstDateStr=null, sourceXml=null, magXml=null, createTime=1789981625819, creator=13701087609, updateTime=1789981625819, updator=13701087609, issue=Issue{id=1308840985296204417, tenantId=1146029695717560320, journalId=1189982191388893191, year='2026', volume='61', issue='5', pageStart='1435', pageEnd='1880', issueExtLink='null', onlineDate='null', pubDate='1778515200000', pubDateStr='2026-05-12', beforeIssueId=null, nextIssueId=null, price=null, status=1, issueComplete=1, articleOrder=1, issueType=-1, specialIssue=null, createTime=1789981607984, creator='13701087609', updateTime=1789984207975, updator='13701087609', preIssue=null, nextIssue=null, articleTotal=null, ext={EN=IssueExt(id=1308851890515968861, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840985296204417, language=EN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=), CN=IssueExt(id=1308851890515968862, tenantId=1146029695717560320, journalId=1189982191388893191, issueId=1308840985296204417, language=CN, specialIssueTitle=, coverIllustrator=null, specialIssueEditor=, specialIssueAbout=)}, issueFiles=null, downloadFileDto=null}, startPage=1542, endPage=1549, ext={EN=ArticleExt(id=1308841061699641955, articleId=1308841060105806434, tenantId=1146029695717560320, journalId=1189982191388893191, language=EN, title=Application of bioorthogonal chemistry in targeted protein degradation, columnId=1190335348648547107, journalTitle=Acta Pharmaceutica Sinica, columnName=Reviews, runingTitle=null, highlight=null, articleAbstract=

Disruption of protein homeostasis is a central pathological mechanism in a variety of major diseases. However, traditional small-molecule inhibitors are often limited by issues such as undruggable targets and drug resistance, falling short of clinical needs. Targeted protein degradation (TPD) technologies offer a promising alternative by eliminating pathogenic proteins and thus overcoming key bottlenecks in conventional drug development. Among these, proteolysis-targeting chimera (PROTAC), which hijack the ubiquitin–proteasome system to degrade target proteins, have shown significant translational potential in the treatment of cancer and immune-related disorders. To further enhance the specificity and therapeutic index of PROTAC, bioorthogonal strategies have been increasingly explored in recent years for the development of next-generation degraders. These approaches not only reduce systemic toxicity but also enable spatiotemporal precision control, offering new avenues for the rational design of PROTAC.

, authors=Qian-lin YANG1, Hao-xing WU1, Qi-long ZHOU2, *, authorsList=Qian-lin YANG, Hao-xing WU, Qi-long ZHOU, authorCompany=null, correspAuthors=Qi-long ZHOU, authorNote=null, correspAuthorsNote=null, copyrightStatement=Copyright ©2026 Acta Pharmaceutica Sinica. All rights reserved., copyrightOwner=null, extLink=null, articleAbsUrl=null, sourceXml=null, magXml=null, pdfUrl=null, pdf=null, pdfFileSize=null, pdfExtLink=null, richHtmlUrl=null, mobilePdfUrl=null, reviewReport=null, pdfFirstPage=null, abstractGraph=null, abstractGraphContent=null, abstractVideo=null, citation=null, cebUrl=null, magXmlContent=null, mapNumber=null, fund=null), CN=ArticleExt(id=1308841062886629996, articleId=1308841060105806434, tenantId=1146029695717560320, journalId=1189982191388893191, language=CN, title=生物正交化学在靶向蛋白降解中的应用, columnId=1190335349655180086, journalTitle=药学学报, columnName=综述, runingTitle=null, highlight=null, articleAbstract=

蛋白质稳态失衡是多种重大疾病的核心病理机制, 传统小分子抑制剂因“不可成药”靶点与耐药等局限难以满足临床需求。靶向蛋白降解技术(targeted protein degradation, TPD)可通过清除异常蛋白突破传统小分子抑制剂面临的新药开发瓶颈。其中蛋白降解靶向嵌合体(proteolysis-targeting chimera, PROTAC)技术借助泛素-蛋白酶体系统实现靶蛋白降解, 在肿瘤及免疫疾病治疗领域展现出临床转化潜力。为进一步提高PROTAC治疗的靶向性, 本文将总结近年来应用于新型PROTAC开发的生物正交策略, 这些策略不但可有效降低系统毒性还能提升特异性实现时空精准调控, 为PROTAC的设计提供新路径。

, authors=杨茜麟1, 吴昊星1, 周启龙2, *, authorsList=杨茜麟, 吴昊星, 周启龙, authorCompany=null, correspAuthors=周启龙, authorNote=

作者贡献:

杨茜麟负责文献调研、整理归纳及撰写文章初稿; 吴昊星负责文章修改及系统分析; 周启龙负责项目管理及文章思路指导。

, correspAuthorsNote=
周启龙, Tel: 15680903786, E-mail:
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tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, language=CN, orderNo=5, keyword=蛋白降解时空调控)], refs=[Reference(id=1308841067554890389, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=1, rfOrder=0, authorNames=null, journalName=null, refType=null, unstructuredReference=Listov D, Goverde CA, Correia BE, et al. Opportunities and challenges in design and optimization of protein function [J]. Nat Rev Mol Cell Biol, 2024, 25: 639-653., articleTitle=null, refAbstract=null), Reference(id=1308841067768799894, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=2, rfOrder=1, authorNames=null, journalName=null, refType=null, unstructuredReference=Huang XD, Dixit VM. Drugging the undruggables: Exploring the ubiquitin system for drug development [J]. Cell Res, 2016, 26: 484-498., articleTitle=null, refAbstract=null), Reference(id=1308841067861074583, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=3, rfOrder=2, authorNames=null, journalName=null, refType=null, unstructuredReference=Sogbein O, Paul P, Umar M, et al. Bortezomib in cancer therapy: Mechanisms, side effects, and future proteasome inhibitors [J]. Life Sci, 2024, 358: 123125., articleTitle=null, refAbstract=null), Reference(id=1308841067923989144, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=4, rfOrder=3, authorNames=null, journalName=null, refType=null, unstructuredReference=Zhang C, Liu YB, Li GC, et al. Targeting the undruggables-the power of protein degraders [J]. Sci Bull (Beijing), 2024, 69: 1776-1797., articleTitle=null, refAbstract=null), Reference(id=1308841067995292313, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=5, rfOrder=4, authorNames=null, journalName=null, refType=null, unstructuredReference=Ciechanover A, Heller H, Elias S, et al. ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation [J]. Proc Natl Acad Sci U S A, 1980, 77: 1365-1368., articleTitle=null, refAbstract=null), Reference(id=1308841068054012570, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=6, rfOrder=5, authorNames=null, journalName=null, refType=null, unstructuredReference=Hershko A, Ciechanover A, Heller H, et al. Proposed role of ATP in protein breakdown: Conjugation of proteins with multiple chains of the polypeptide of ATP-dependent proteolysis [J]. Proc Natl Acad Sci U S A, 1980, 77: 1783-1786., articleTitle=null, refAbstract=null), Reference(id=1308841068129510043, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=7, rfOrder=6, authorNames=null, journalName=null, refType=null, unstructuredReference=Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation [J]. Proc Natl Acad Sci U S A, 2001, 98: 8554-8559., articleTitle=null, refAbstract=null), Reference(id=1308841068221784732, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=8, rfOrder=7, authorNames=null, journalName=null, refType=null, unstructuredReference=Schreiber SL. The rise of molecular glues [J]. Cell, 2021, 184: 3-9., articleTitle=null, refAbstract=null), Reference(id=1308841068293087901, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=9, rfOrder=8, authorNames=null, journalName=null, refType=null, unstructuredReference=Banik SM, Pedram K, Wisnovsky S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins [J]. Nature, 2020, 584: 291-297., articleTitle=null, refAbstract=null), Reference(id=1308841068372779678, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=10, rfOrder=9, authorNames=null, journalName=null, refType=null, unstructuredReference=Schapira M, Calabrese MF, Bullock AN, et al. Targeted protein degradation: Expanding the toolbox [J]. Nat Rev Drug Discov, 2019, 18: 949-963., articleTitle=null, refAbstract=null), Reference(id=1308841068435694239, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=11, rfOrder=10, authorNames=null, journalName=null, refType=null, unstructuredReference=Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics [J]. Nat Chem Biol, 2019, 15: 937-944., articleTitle=null, refAbstract=null), Reference(id=1308841068502803104, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=12, rfOrder=11, authorNames=null, journalName=null, refType=null, unstructuredReference=Liu JH, Chen YM, Cai XQ. Research advances in new technologies in targeted protein degradation [J]. Acta Pharm Sin (药学学报), 2022, 57: 313-320., articleTitle=null, refAbstract=null), Reference(id=1308841068578300577, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=13, rfOrder=12, authorNames=null, journalName=null, refType=null, unstructuredReference=Johnson DS, Weerapana E, Cravatt BF. Strategies for discovering and derisking covalent, irreversible enzyme inhibitors [J]. Future Med Chem, 2010, 2: 949-964., articleTitle=null, refAbstract=null), Reference(id=1308841068645409442, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=14, rfOrder=13, authorNames=null, journalName=null, refType=null, unstructuredReference=Zeng SX, Huang WH, Zheng XL, et al. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges [J]. Eur J Med Chem, 2021, 210: 112981., articleTitle=null, refAbstract=null), Reference(id=1308841068704129699, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=15, rfOrder=14, authorNames=null, journalName=null, refType=null, unstructuredReference=Yang YQ, Gao HY, Sun XY, et al. Global PROTAC toolbox for degrading BCR-ABL overcomes drug-resistant mutants and adverse effects [J]. J Med Chem, 2020, 63: 8567-8583., articleTitle=null, refAbstract=null), Reference(id=1308841068783821476, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=16, rfOrder=15, authorNames=null, journalName=null, refType=null, unstructuredReference=Wu JJ, Hu JP. Pharmacokinetics of PROTACs and their research progress in disease treatment [J]. Acta Pharm Sin (药学学报), 2024, 59: 2484-2490., articleTitle=null, refAbstract=null), Reference(id=1308841070516069029, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=17, rfOrder=16, authorNames=null, journalName=null, refType=null, unstructuredReference=Wilkinson KD. The discovery of ubiquitin-dependent proteolysis [J]. Proc Natl Acad Sci U S A, 2005, 102: 15280-15282., articleTitle=null, refAbstract=null), Reference(id=1308841070599955110, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=18, rfOrder=17, authorNames=null, journalName=null, refType=null, unstructuredReference=Tooze SA, Dikic I. Autophagy captures the nobel prize [J]. Cell, 2016, 167: 1433-1435., articleTitle=null, refAbstract=null), Reference(id=1308841070675452583, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=19, rfOrder=18, authorNames=null, journalName=null, refType=null, unstructuredReference=Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy [J]. Science, 2019, 366: 818-822., articleTitle=null, refAbstract=null), Reference(id=1308841070784504488, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=20, rfOrder=19, authorNames=null, journalName=null, refType=null, unstructuredReference=Qin H, Zhang YW, Lou YT, et al. Overview of PROTACs targeting the estrogen receptor: Achievements for biological and drug discovery [J]. Curr Med Chem, 2022, 29: 3922-3944., articleTitle=null, refAbstract=null), Reference(id=1308841070876779177, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=21, rfOrder=20, authorNames=null, journalName=null, refType=null, unstructuredReference=Salvaris RT, Brennan J, Lewis KL. BTK is the target that keeps on giving: A review of BTK-degrader drug development, clinical data, and future directions in CLL [J]. Cancers (Basel), 2025, 17: 557., articleTitle=null, refAbstract=null), Reference(id=1308841070990025386, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=22, rfOrder=21, authorNames=null, journalName=null, refType=null, unstructuredReference=Ackerman L, Acloque G, Bacchelli S, et al. IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: A phase 1 trial [J]. Nat Med, 2023, 29: 3127-3136., articleTitle=null, refAbstract=null), Reference(id=1308841071065522859, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=23, rfOrder=22, authorNames=null, journalName=null, refType=null, unstructuredReference=Hinova Pharmaceuticals Inc. A phase Ⅰ/Ⅱ trial to evaluate oral HP568 tablets in patients with ER+/HER2 advanced breast cancer [EB/OL]. (2025-01-03) [2025-05-26]. https://clinicaltrials.gov/study/NCT06757335?term=T06757335&rank=1., articleTitle=null, refAbstract=null), Reference(id=1308841071153603244, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=24, rfOrder=23, authorNames=null, journalName=null, refType=null, unstructuredReference=Haisco Pharmaceutical Group Co., Ltd. Phase I study of HSK40118 in NSCLC patients with EGFR mutation [EB/OL]. (2023-09-22) [2025-05-26]. https://clinicaltrials.gov/study/NCT06050980#study-overviews., articleTitle=null, refAbstract=null), Reference(id=1308841071233295021, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=25, rfOrder=24, authorNames=null, journalName=null, refType=null, unstructuredReference=Krönke J, Udeshi N, Narla A, et al. Lenalidomide promotes CRBN-mediated ubiquitination and degradation of IKZF1 and IKZF3 [J]. Blood, 2013, 122: LBA-5., articleTitle=null, refAbstract=null), Reference(id=1308841071308792494, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=26, rfOrder=25, authorNames=null, journalName=null, refType=null, unstructuredReference=Takahashi D, Moriyama J, Nakamura T, et al. AUTACs: Cargo-specific degraders using selective autophagy [J]. Mol Cell, 2019, 76: 797-810. e 710., articleTitle=null, refAbstract=null), Reference(id=1308841071375901359, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=27, rfOrder=26, authorNames=null, journalName=null, refType=null, unstructuredReference=Li ZY, Zhu CG, Ding Y, et al. ATTEC: A potential new approach to target proteinopathies [J]. Autophagy, 2019, 16: 185-187., articleTitle=null, refAbstract=null), Reference(id=1308841071447204528, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=28, rfOrder=27, authorNames=null, journalName=null, refType=null, unstructuredReference=Schiedel M, Herp D, Hammelmann S, et al. Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals) [J]. J Med Chem, 2017, 61: 482-491., articleTitle=null, refAbstract=null), Reference(id=1308841071518507697, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=29, rfOrder=28, authorNames=null, journalName=null, refType=null, unstructuredReference=Peng ZQ, Fang W, Wu B, et al. Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer [J]. Nat Chem Biol, 2024, 21: 59-70., articleTitle=null, refAbstract=null), Reference(id=1308841071606588082, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=30, rfOrder=29, authorNames=null, journalName=null, refType=null, unstructuredReference=Teng XC, Zhao X, Dai YC, et al. ClickRNA-PROTAC for tumor-selective protein degradation and targeted cancer therapy [J]. J Am Chem Soc, 2024, 146: 27382-27391., articleTitle=null, refAbstract=null), Reference(id=1308841071694668467, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=31, rfOrder=30, authorNames=null, journalName=null, refType=null, unstructuredReference=Mou Y, Wen S, Wang Y, et al. Research progress in controllable proteolysis targeting chimeras [J]. Acta Pharm Sin (药学学报), 2023, 58: 2193-2202., articleTitle=null, refAbstract=null), Reference(id=1308841071757583028, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=32, rfOrder=31, authorNames=null, journalName=null, refType=null, unstructuredReference=Bauer D, Sarrett SM, Lewis JS, et al. Click chemistry: A transformative technology in nuclear medicine [J]. Nat Protoc, 2023, 18: 1659-1668., articleTitle=null, refAbstract=null), Reference(id=1308841071841469109, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=33, rfOrder=32, authorNames=null, journalName=null, refType=null, unstructuredReference=Sletten EM, Bertozzi CR. From mechanism to mouse: A tale of two bioorthogonal reactions [J]. Acc Chem Res, 2011, 44: 666-676., articleTitle=null, refAbstract=null), Reference(id=1308841071946326710, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=34, rfOrder=33, authorNames=null, journalName=null, refType=null, unstructuredReference=Agard NJ, Prescher JA, Bertozzi CR. A strain-promoted [3+2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems [J]. J Am Chem Soc, 2004, 126: 15046-15047., articleTitle=null, refAbstract=null), Reference(id=1308841072021824183, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=35, rfOrder=34, authorNames=null, journalName=null, refType=null, unstructuredReference=Scinto SL, Bilodeau DA, Hincapie R, et al. Bioorthogonal chemistry [J]. Nat Rev Methods Primers, 2021, 1: 30., articleTitle=null, refAbstract=null), Reference(id=1308841072114098872, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=36, rfOrder=35, authorNames=null, journalName=null, refType=null, unstructuredReference=Kim E, Koo H. Biomedical applications of copper-free click chemistry: In vitro, in vivo, and ex vivo [J]. Chem Sci, 2019, 10: 7835-7851., articleTitle=null, refAbstract=null), Reference(id=1308841072265093817, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=37, rfOrder=36, authorNames=null, journalName=null, refType=null, unstructuredReference=Oliveira BL, Guo Z, Bernardes GJL. Inverse electron demand Diels-Alder reactions in chemical biology [J]. Chem Soc Rev, 2017, 46: 4895-4950., articleTitle=null, refAbstract=null), Reference(id=1308841072336396986, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=38, rfOrder=37, authorNames=null, journalName=null, refType=null, unstructuredReference=He XY, Li J, Liang XX, et al. An all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction [J]. Nat Commun, 2024, 15: 2831., articleTitle=null, refAbstract=null), Reference(id=1308841072432865979, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=39, rfOrder=38, authorNames=null, journalName=null, refType=null, unstructuredReference=Deng YQ, Shen TR, Yu XY, et al. Tetrazine‐isonitrile bioorthogonal fluorogenic reactions enable multiplex labeling and wash-free bioimaging of live cells [J]. Angew Chem Int Ed Engl, 2024, 63: e202319853., articleTitle=null, refAbstract=null), Reference(id=1308841072512557756, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=40, rfOrder=39, authorNames=null, journalName=null, refType=null, unstructuredReference=Tu JL, Xu MH, Parvez S, et al. Bioorthogonal removal of 3-isocyanopropyl groups enables the controlled release of fluorophores and drugs in vivo [J]. J Am Chem Soc, 2018, 140: 8410-8414., articleTitle=null, refAbstract=null), Reference(id=1308841072604832445, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=41, rfOrder=40, authorNames=null, journalName=null, refType=null, unstructuredReference=Lebraud H, Wright DJ, Johnson CN, et al. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras [J]. ACS Cent Sci, 2016, 2: 927-934., articleTitle=null, refAbstract=null), Reference(id=1308841072692912830, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=42, rfOrder=41, authorNames=null, journalName=null, refType=null, unstructuredReference=Wurz RP, Dellamaggiore K, Dou H, et al. A "click chemistry platform" for the rapid synthesis of bispecific molecules for inducing protein degradation [J]. J Med Chem, 2017, 61: 453-461., articleTitle=null, refAbstract=null), Reference(id=1308841072768410303, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=43, rfOrder=42, authorNames=null, journalName=null, refType=null, unstructuredReference=Chang MY, Gao F, Pontigon D, et al. Bioorthogonal PROTAC prodrugs enabled by on-target activation [J]. J Am Chem Soc, 2023, 145: 14155-14163., articleTitle=null, refAbstract=null), Reference(id=1308841072856490688, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=44, rfOrder=43, authorNames=null, journalName=null, refType=null, unstructuredReference=Gao J, Hou B, Zhu Q, et al. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy [J]. Nat Commun, 2022, 13: 4318., articleTitle=null, refAbstract=null), Reference(id=1308841072944571073, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=45, rfOrder=44, authorNames=null, journalName=null, refType=null, unstructuredReference=Jin YH, Fan J, Wang RY, et al. Ligation to scavenging strategy enables on-demand termination of targeted protein degradation [J]. J Am Chem Soc, 2023, 145: 7218-7229., articleTitle=null, refAbstract=null), Reference(id=1308841073011679938, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=46, rfOrder=45, authorNames=null, journalName=null, refType=null, unstructuredReference=Xie SW, Zhu JJ, Peng YH, et al. In vivo self-assembly of PROTACs by bioorthogonal chemistry for precision cancer therapy [J]. Angew Chem Int Ed Engl, 2025, 64: e202421713., articleTitle=null, refAbstract=null), Reference(id=1308841073082983107, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=47, rfOrder=46, authorNames=null, journalName=null, refType=null, unstructuredReference=Xiong Y, Zhong Y, Yim H, et al. Bridged proteolysis targeting chimera (PROTAC) enables degradation of undruggable targets [J]. J Am Chem Soc, 2022, 144: 22622-22632., articleTitle=null, refAbstract=null), Reference(id=1308841073145897668, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=48, rfOrder=47, authorNames=null, journalName=null, refType=null, unstructuredReference=Yang ZH, Chen M, Ge RX, et al. Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation [J]. Nat Commun, 2025, 16: 2494., articleTitle=null, refAbstract=null), Reference(id=1308841073204617925, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=49, rfOrder=48, authorNames=null, journalName=null, refType=null, unstructuredReference=Yan XJ, Li Y, Wang GB, et al. Molecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1 [J]. Mol Cell, 2021, 81: 3262-3274.e 3263., articleTitle=null, refAbstract=null), Reference(id=1308841073271726790, tenantId=1146029695717560320, journalId=1189982191388893191, articleId=1308841060105806434, doi=null, pmid=null, pmcid=null, year=null, volume=null, issue=null, pageStart=null, pageEnd=null, url=null, language=null, rfNumber=50, rfOrder=49, authorNames=null, journalName=null, refType=null, unstructuredReference=Yang FF, Luo QH, Wang YC, et al. 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A: pH- and MMP-responsive IEDDA reaction promotes targeted degradation by PROTACs; B: Light-responsive PROTAC-based nano-drug delivery system; C: Self-assembly of PROTACs via the "split-and-mix" strategy; D: The "ligation to scavenging" strategy terminates the degradation process by capturing free PROTAC molecules through Tz-TCO click reaction. 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生物正交化学在靶向蛋白降解中的应用
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杨茜麟 1 , 吴昊星 1 , 周启龙 2, *
药学学报 | 综述 2026,61(5): 1542-1549
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药学学报 |综述 2026 , 61 (5) : 1542 -1549
生物正交化学在靶向蛋白降解中的应用
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杨茜麟1, 吴昊星1, 周启龙2, *
作者信息
  • 1四川大学华西医院磁共振研究中心, 放射影像研究所, 四川 成都 610041
  • 2四川大学华西医院天然与仿生药物研究中心, 四川 成都 610041
通讯作者:
周启龙, Tel: 15680903786, E-mail:
作者简介:

作者贡献:

杨茜麟负责文献调研、整理归纳及撰写文章初稿; 吴昊星负责文章修改及系统分析; 周启龙负责项目管理及文章思路指导。

Application of bioorthogonal chemistry in targeted protein degradation
Qian-lin YANG1, Hao-xing WU1, Qi-long ZHOU2, *
Affiliations
  • 1Institute of Radiology and Medical Imaging, Huaxi MR Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
  • 2Natural and Biomimetic Medicine Research Center, West China Hospital, Sichuan University, Chengdu 610041, China
出版时间: 2026-05-12 doi: 10.16438/j.0513-4870.2025-0597
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摘要
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蛋白质稳态失衡是多种重大疾病的核心病理机制, 传统小分子抑制剂因“不可成药”靶点与耐药等局限难以满足临床需求。靶向蛋白降解技术(targeted protein degradation, TPD)可通过清除异常蛋白突破传统小分子抑制剂面临的新药开发瓶颈。其中蛋白降解靶向嵌合体(proteolysis-targeting chimera, PROTAC)技术借助泛素-蛋白酶体系统实现靶蛋白降解, 在肿瘤及免疫疾病治疗领域展现出临床转化潜力。为进一步提高PROTAC治疗的靶向性, 本文将总结近年来应用于新型PROTAC开发的生物正交策略, 这些策略不但可有效降低系统毒性还能提升特异性实现时空精准调控, 为PROTAC的设计提供新路径。

生物正交化学  /  靶向蛋白降解  /  蛋白降解靶向嵌合体  /  降解剂设计  /  蛋白降解时空调控

Disruption of protein homeostasis is a central pathological mechanism in a variety of major diseases. However, traditional small-molecule inhibitors are often limited by issues such as undruggable targets and drug resistance, falling short of clinical needs. Targeted protein degradation (TPD) technologies offer a promising alternative by eliminating pathogenic proteins and thus overcoming key bottlenecks in conventional drug development. Among these, proteolysis-targeting chimera (PROTAC), which hijack the ubiquitin–proteasome system to degrade target proteins, have shown significant translational potential in the treatment of cancer and immune-related disorders. To further enhance the specificity and therapeutic index of PROTAC, bioorthogonal strategies have been increasingly explored in recent years for the development of next-generation degraders. These approaches not only reduce systemic toxicity but also enable spatiotemporal precision control, offering new avenues for the rational design of PROTAC.

bioorthogonal chemistry  /  targeted protein degradation  /  proteolysis-targeting chimera  /  degrader design  /  spatiotemporal control of protein degradation
杨茜麟, 吴昊星, 周启龙. 生物正交化学在靶向蛋白降解中的应用. 药学学报, 2026 , 61 (5) : 1542 -1549 . DOI: 10.16438/j.0513-4870.2025-0597
Qian-lin YANG, Hao-xing WU, Qi-long ZHOU. Application of bioorthogonal chemistry in targeted protein degradation[J]. Acta Pharmaceutica Sinica, 2026 , 61 (5) : 1542 -1549 . DOI: 10.16438/j.0513-4870.2025-0597
正文
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蛋白质是生命活动的核心执行者, 通过分级动态网络精确协调细胞功能[1]。其调控体系涵盖基因转录调控、翻译后修饰、亚细胞定位及蛋白酶体降解等精密环节。该过程赋予蛋白质功能可塑性, 但也使其稳定性面临多重挑战。蛋白质稳态失衡主要源于三大病理机制: 基因突变导致三维构象异常, 分子伴侣系统缺陷引发错误折叠或聚集, 信号转导网络失调导致过度活化, 这些异常状态驱动了从神经退行性疾病、代谢综合征到恶性肿瘤等多种疾病的发病进程[2]。针对蛋白质异常活化的病理特征, 当前临床主要依赖小分子抑制剂干预, 然而, 小分子药物易诱发靶点耐药性突变、存在脱靶毒性, 且约80%疾病相关蛋白缺乏活性口袋属于“不可成药”靶点, 凸显了现有治疗策略的局限[3, 4] (图1)。
20世纪末, Ciechanover等[5]和Hershko等[6]揭示了泛素介导的蛋白降解机制, 其依赖E1-E2-E3三级酶联反应实现泛素化标记, 由26S蛋白酶体高效水解错误折叠蛋白及短寿命调节蛋白, 开辟了泛素-蛋白酶体系统(ubiquitin-proteasome system, UPS)这一全新的蛋白调控研究领域, 不仅革新了对蛋白动态平衡的认知, 更为后续TPD技术的诞生奠定了理论基础(图1)。随着该领域的发展, 2001年Sakamoto等[7]首创蛋白降解靶向嵌合体技术(proteolysis-targeting chimera, PROTAC), 此后分子胶(molecular glue)技术[8]、自噬-溶酶体降解途径(lysosomal pathway, LP)[9]等新型降解策略相继涌现, 共同构建了多维度蛋白降解调控体系[10, 11]。与传统小分子抑制剂药物相比, 蛋白降解技术展现了多种优势[12]: 通过靶向降解而非单纯抑制“难治性”蛋白, 突破了“不可成药”靶点限制; 降解过程不依赖持续占据活性位点, 可有效规避靶点突变引发的药物抵抗, 有望克服耐药性难题; 降解剂分子循环催化多个靶蛋白的清除, 实现亚化学计量效应, 从而降低给药剂量并延长作用时效。相较于常规疗法, 蛋白降解技术对疾病中异常蛋白堆积清除展现出显著优势, 随着分子结构优化技术的进步和递送系统精准度的提升, 该领域成为突破传统药物治疗瓶颈的新手段[13-15]。目前, PROTAC药物在肿瘤、神经退行性疾病、心血管疾病和病毒感染等疾病中均表现出良好的治疗效果及巨大的潜力[16]。
1　靶向蛋白降解技术的理论基础与应用
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细胞内蛋白降解主要依赖UPS[17]和LP[18]两大核心机制(图2)。UPS依赖蛋白酶体快速水解泛素化标记蛋白, 如错误折叠蛋白、短寿命调节蛋白等, 而LP通过溶酶体介导的吞噬、自噬或内吞作用, 清除UPS难以处理的大分子复合物及细胞器, 如蛋白聚集体、脂滴、受损线粒体等[19]。二者通过差异化的底物偏好实现功能互补、作用协同, 共同保障细胞内环境的动态平衡。
1.1　基于泛素-蛋白酶体系统的降解策略
基于UPS的蛋白降解技术以PROTAC和分子胶为代表, 通过泛素化标记实现目标蛋白(protein of interest, POI)的靶向降解。PROTAC作为双功能分子桥接靶蛋白与E3泛素连接酶(VHL或CRBN等), 诱导靶蛋白泛素化并招募蛋白酶体降解, 其催化特性可在低剂量下持续作用, 有望克服传统抑制剂导致的耐药性突变。目前已有多种PROTAC药物进入临床试验阶段, 其中, 辉瑞/Arvinas研发靶向ER的ARV-471[20], 以及由百济神州发现靶向BTK的BGB-16673[21], 分别用于治疗ER+/HER2-型乳腺癌和复发/难治性慢性淋巴细胞白血病(chronic lymphocytic leukemia, CLL/small lymphocytic lymphoma, SLL), 均已进入Ⅲ期临床; Kymera的KT-474靶向IRAK4, 用于治疗化脓性汗腺炎和特应性皮炎, 正处于Ⅱ期临床[22]; 此外, 海创药业的HP568片靶向Erα用于晚期乳腺癌的治疗[23]、海思科研发的全球首款EGFR-PROTAC HSK40118片用于治疗EGFR突变非小细胞肺癌[24], 已分别进入Ⅰ/Ⅱ期和Ⅰ期临床。相比之下, 分子胶的分子质量较小, 具有更优异的组织渗透性, 其通过分别结合E3连接酶和靶蛋白表面, 诱导二者非天然结合形成三元复合物, 促使POI降解。1991年, Schreiber[8]首次发现了分子胶(环孢菌素A), 可同时结合亲环素(cyclophilin, CypA)和钙调节神经磷酸酶(calcineurin, CN), 抑制钙调神经磷酸酶的活性, 从而阻断T细胞激活, 实现免疫抑制。然后, Celgene公司开发的来那度胺于2005年被FDA批准上市, 成功用于降解多发性骨髓瘤中的IKZF1/3蛋白[25]。
1.2　基于溶酶体途径的降解策略
与UPS的降解底物不同, LP则通过自噬体包裹、内吞或吞噬作用, 由溶酶体降解, 主要聚焦大分子或细胞器水平的清除: Arimoto团队[26]开发设计的自噬靶向嵌合体(autophagosome-targeting chimera, AUTAC), 通过诱导靶蛋白的K63位点泛素化标记以及模拟S-鸟苷酸化修饰激活自噬体包裹靶标(如线粒体碎片)并降解, 但其降解速率较UPS技术滞后, 且机制不明确具有脱靶风险; 溶酶体靶向嵌合体(lysosome-targeting chimera, LYTAC)利用抗体或肽段靶向膜蛋白PD-L1并连接溶酶体分选受体, Bertozzi团队[9]提出将阳离子非依赖性甘露糖-6-磷酸受体(cation-independent mannose-6-phosphate receptor, CI-M6PR)与靶蛋白连接, 通过受体介导的内吞作用将靶蛋白转运至溶酶体降解, 然而, 该方法需优化偶联位点以平衡靶向性与药代动力学特性; 自噬体拴系化合物(autophagosome tethering compound, ATTEC)通过直接拴系靶标与自噬体标志蛋白mATG8, 绕开泛素化步骤实现降解, 2019年, 鲁伯埙团队[27]报道了一系列可连接突变huntingtin蛋白(mutant huntingtin, mHTT)和LC3的ATTEC分子, 例如10O5 (GW), AN1, AN2等, 但分子设计成本高限制了临床应用。LP技术为蛋白降解剂的设计提供了新思路, 但仍需深入验证其作用机制, 优化其设计, 提升精准性, 与UPS技术联用有望突破单一降解通路的局限。
2　生物正交化学重塑蛋白降解技术调控体系
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作为最成熟的蛋白降解技术, PROTAC已覆盖多种疾病研究领域, 然而其跨膜渗透效率较低、E3泛素连接酶选择有限, 导致临床应用受限。近年来, 多学科交叉的技术革新为突破PROTAC成药性壁垒提供了解决方案。2017年铜催化叠氮-炔环加成(Cu-catalyzed azide-alkyn cycloaddition, CuAAC)首次实现PROTAC模块化合成, 奠定了精准设计降解剂的基础[28]; 2020年后AI技术发展迅速, 如清华大学SMART1联合PD-1抑制剂的智能筛选, 通过深度学习优化分子结合效率, 大大缩短了PROTAC的开发周期[29]; 至2024年“点击化学”及“生物正交化学”驱动的“点击PROTAC”通过光控激活、肿瘤微环境靶向偶联等策略, 实现了POI时空特异性降解, 突破了传统药代屏障, 降低了脱靶不良反应[30](图3)。因此, “点击PROTAC”有望凭借动态可控的精准修饰能力[31], 解决PROTAC的渗透性与选择性难题, 推动TPD技术从技术突破、精准递送、效能调控、应用拓展到工艺革新的全面发展。
2.1　生物正交反应助力“点击PROTAC”技术突破
“点击化学”(click chemistry)由Sharpless和Meldal于2001年提出, 通过高效、立体专一的铜催化叠氮-炔环加成反应实现分子选择性组装, 然而对铜催化剂依赖限制了其在生物体系中的应用[32]。针对此局限, Sletten等[33]于2011年提出“生物正交化学”概念, 可在生理环境中特异性发生, 不干扰内源性生化过程, 其标志性反应包括: 基于应变促进叠氮-炔环加成(strain-promoted azide-alkyne cycloaddition, SPAAC), 可避免金属催化剂导致的细胞毒性[34], 虽反应速率相对较低(k ≈ 10-2~1 mol·L-1·s-1), 但其不依赖催化剂, 适用于体外生物标记以及对系统毒性要求严苛的体内应用; 逆电子需求狄尔斯-阿尔德反应(inverse-electron-demand Diels-Alder reaction, IEDDA), 该反应通常发生在四嗪(tetrazine, Tz)与反式环辛烯(trans-cyclooctene, TCO)等亲二烯体之间, 具备超高反应速率(k ≈ 103~106 mol·L-1·s-1)及出色的生理稳定性, 尤其适合胞内原位构建“点击PROTAC”用于肿瘤或特定微环境下的快速活化[35], 可实现活细胞和活体内生物分子的精准标记和靶向治疗[36-38]。不仅如此, Tz还可与异腈发生[4+1] 生物正交反应, 实现对细胞器的多重正交标记[39, 40]。以上反应奠定了生物正交化学在复杂生物环境中系统中可控修饰的基础。
由于PROTAC依赖靶蛋白、降解剂与E3连接酶形成三元复合物以启动泛素-蛋白酶体降解途径, 因此其效能受连接子空间构象的限制, 同时面临分子细胞渗透性差、“钩效应”干扰以及药代动力学特性不佳等递送难题。基于“生物正交化学”设计思路的“点击PROTAC”通过高选择性的反应活性与模块化合成特性, 可精准调控连接子结构, 利用快速定向的化学偶联优化三元复合物的结合效果, 从而增强降解剂的结构可塑性与靶标结合效率。此外, 其生理环境兼容性支持时空特异性反应需求, 可通过微环境响应策略动态调控降解活性, 显著降低系统性暴露引发的脱靶风险, 优化药物性质与作用效果[41]。
2.2　生物正交反应推动PROTAC精准递送
基于IEDDA的高选择性和快速反应, 生物正交将PROTAC拆分成功能模块(靶点配体、E3配体), 通过原位组装策略, 让两个模块在特定的目标部位启动点击反应形成活性PROTAC, 使其在病灶区域精准递送以降低系统毒性。更重要的是, 将“点击PROTAC”与智能响应型设计思路结合, 可实现PROTAC的动态组装与靶向激活, 构建多机制协同的精准递送系统(图4A)。Heightman团队[41]首创的细胞内点击形成的蛋白水解靶向嵌合体(in-cell click-formed proteolysis targeting chimeras, CLIPTAC)策略将传统PROTAC分解为靶标结合模块(Tz标记配体)与E3连接酶募集模块(TCO标记配体), 利用点击化学实现胞内原位组装。这种“分裂式设计”在简化合成流程的同时, 依赖肿瘤微环境特异性反应降低了系统性暴露风险[42]。王卫课题组[43]进一步开发的“Click-Release”型前药CR-PROTACs, 通过RGD-Tz肽与TCO修饰前药的生物正交反应实现肿瘤靶向释放, 大大提升了ARV-771在结直肠癌模型中的肿瘤/血浆浓度, 降低对正常组织毒性(图4B)。此外, 于海军团队[44]构建的POLY-PROTAC纳米粒通过三重响应机制, 即基质金属蛋白酶2 (matrix metalloproteinase-2, MMP-2)酶切、pH敏感、GSH还原实现了药物的精准递送, 其负载的BRD4-PROTAC在乳腺癌模型中展现出显著优于游离药物的降解效率, 与光动力疗法(PDT)联合, 有效抑制了肿瘤生长。
2.3　生物正交反应赋能PROTAC功能动态调控
在实现精准递送的基础上, “点击PROTAC”利用“生物正交反应”的可逆性与时空响应特性, 可进一步开发针对PROTAC活性的动态调控技术, 解决PROTAC可能存在的持续作用导致过度降解、无法按需调控的问题, 实现更精准的时空调控, 降低潜在不良反应, 为治疗提供更高安全窗。尤启冬团队[45]采用的“Ligation to Scavenging”策略通过Tz-TCO点击反应快速捕获游离PROTAC分子, 实现了降解过程的即时终止(图4D)。该系统在帕金森病模型中可将α-synuclein蛋白水平调控在生理阈值范围内, 为神经退行性疾病的动态治疗提供了新思路。徐盛涛团队[46]开发了一种基于生物正交化学的Nano-CLIPTACs策略, 通过将传统大分子PROTACs拆分为两个可自组装的前体药物(ALE-TCO和POM-Tz), 利用cRGD肽修饰的脂质体进行肿瘤靶向递送, 在肿瘤细胞内通过IEDDA反应原位形成功能型PROTACs, 成功实现了间变性淋巴瘤激酶(anaplastic lymphoma kinase, ALK)的特异性降解, 该策略有效克服了传统PROTACs的脱靶毒性、药物动力学性质差和“钩效应”等瓶颈, 在H3122和Karpas 299异种移植模型中表现出显著抑瘤效果, 同时通过可控释放机制避免了高浓度下无效二聚体的形成, 为PROTAC的临床转化提供了新型精准递送与激活模式。
2.4　生物正交反应拓展PROTAC的应用范围
为克服传统PROTAC对靶蛋白结合位点的依赖性, “点击PROTAC”结合分子互作技术与连接酶库, 可构建“不可成药”靶点降解的技术平台, 突破PROTAC技术面临的“不可成药靶点”这一根本性限制, 扩展PROTAC的适用范围。“Bridged PROTAC”利用小分子结合靶蛋白的邻近复合物, 如CDK4/6-Cyclin D1, 再用生物正交将复合物锚定至E3连接酶。该策略成功降解传统难以靶向的Cyclin D1, 为传统难以成药的转录因子类靶点提供了可行的降解策略[47]。新型E3连接酶的开发, 利用ZATAC技术基于CRL2ZYG11B连接酶开发模块化降解平台, 通过生物正交标记的泛素转移酶配体如ZYG11B配体ZD-4, 与靶蛋白配体动态组装, 实现核仁素NPM1蛋白与突变p53的同步降解, 为拓展E3连接酶库提供了标准化技术手段[48, 49]。
2.5　生物正交化学革新PROTAC开发工艺
通过联用纳米自主装技术, 生物正交联将PROTAC的构建模式从“静态合成”转向“自发动态构建”, 有望实现“合成-筛选-应用”一体化, 为规模化生产与精准应用开辟新路径, 解决PROTAC分子结构复杂、合成困难、筛选周期长、生产成本高的工艺瓶颈, 推动PROTAC从实验室概念向实际药物开发的转化。李子刚团队[50]设计的SM-PROTAC通过多肽自组装形成动态降解复合物, 开发了自组装型降解系统: 其Split-and-Mix特性大大缩短了连接子筛选周期, 为快速开发难成药靶点PROTAC奠定了基础(图4C)。最新报道的Nano-CLIPTACs在肿瘤血管内皮细胞表面通过SPAAC反应原位生成活性PROTAC, 其在肿瘤内的PROTAC浓度是游离组的30倍, 显著提升了肿瘤穿透效率和局部药物浓度且无需复杂纯化工艺[46]。生物正交化学通过动态自组装策略与原位生物正交反应的协同创新, 可实现PROTAC分子构建的时空可控性与模块化合成, 为系统性解决传统降解剂的合成复杂性、递送低效性及脱靶风险提供了新工具, 标志着靶向蛋白降解技术进入智能化精准治疗时代。
3　生物正交联合PROTAC技术的核心挑战与发展方向
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生物正交化学与PROTAC技术的融合为靶向蛋白降解领域带来了革命性进展, 然而其临床转化仍面临多项关键瓶颈, 包括微环境中效率不足、递送系统的组织穿透能力受限, 以及连接子构象对降解活性的动态干扰, 亟待跨学科协同攻克。具体而言, 生物正交反应体系在特定病理微环境中, 低浓度条件下的反应速率限制了有效偶联效率病理微环境中的转化率显著降低, 难以充分生成具有活性的PROTAC分子, 进而削弱其降解效果。与此同时, 由于PROTAC通常具有较高的分子质量和结构复杂性, 现有递送载体对复杂组织屏障的穿透能力和靶向富集效率仍有待提升, 难以保障降解剂前体在靶点处的充分积聚与反应激活, 显著阻碍了其在体内的有效递送和组织分布。更为核心的挑战在于, PROTAC连接子区域的动态构象变化会影响三元复合物的稳定性, 导致降解效率下降, 而目前对于连接子构象与三元复合物稳定性之间的动态关联, 仍缺乏系统性、高通量的筛选与建模手段, 限制了高效PROTAC分子的理性设计与优化开发。
为系统应对上述挑战, 亟需融合化学生物学、材料科学与AI辅助设计等多学科策略。一方面, 可通过优化Tz-TCO或Pyridyl-Tz偶联对开发超快速、高效率的生物正交反应体系, 结合靶向预富集功能的递送载体, 提升在低剂量环境下的反应效率; 另一方面, 构建如红细胞膜伪装纳米载体等仿生递送系统, 整合超声微泡破裂等增强穿透技术, 以提升PROTAC在复杂组织中的递送效果与生物利用度; 此外, 借助DeepPROTAC等先进人工智能模型, 可实现对大规模连接子库的高通量筛选与评估, 精准预测三元复合物的构象稳定性及关键动力学参数, 从而加速高效PROTAC分子的理性设计与优化开发。
4　展望
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生物正交化学与PROTAC技术的结合为靶向蛋白降解开辟了新路径, 通过将传统大分子PROTAC拆分为两个功能模块(即靶蛋白配体与E3连接酶配体), 并在细胞内通过高选择性的生物正交反应实现原位组装, 从而克服高分子质量带来的通透性差、系统毒性及“钩效应”等难题, 并借助靶向递送系统在病灶区域精准富集前体药物, 利用其快速动力学与高特异性在微环境中动态生成活性PROTAC分子, 显著提升局部药物浓度、降低脱靶风险、优化药代动力学特性。然而, 该策略在临床应用中仍面临诸多挑战, 特别是在低浓度微环境中生物正交反应效率不足、递送系统组织穿透能力有限, 以及模块间连接子构象对三元复合物稳定性和降解活性的动态影响。此外, 尽管生物正交反应体系通常被认为具有良好的生理兼容性, 但其潜在毒性与免疫原性不容忽视, 部分未修饰四嗪类化合物可能与内源性代谢物发生非特异性交联, 而SPAAC反应中高环张力的炔烃结构也可能扰乱细胞膜稳定性, 偶联中间体在体内长期残留可能干扰线粒体功能, 甚至诱导氧化应激等。因此, 未来的发展不仅需要化学生物学家开发反应速率更快、生理环境适应性更强的生物正交工具, 也需药物化学家联合人工智能辅助设计平台, 优化PROTAC结构并提升构象预测与三元复合物稳定性评估的效率。基于生物正交化学介导的多重刺激响应递送系统, 结合E3连接酶库的拓展与大数据驱动的筛选算法, 有望实现PROTAC的模式化快速构建, 覆盖更多疾病靶点, 在确保安全性和药效可控的基础上, 进一步提升靶向蛋白降解治疗的精准性, 最终推动其在更多疾病适应症中的临床转化与新药创制。

文献
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参考文献 引证文献
排序方式：
1
Listov D, Goverde CA, Correia BE, et al. Opportunities and challenges in design and optimization of protein function [J]. Nat Rev Mol Cell Biol, 2024, 25: 639-653.
2
Huang XD, Dixit VM. Drugging the undruggables: Exploring the ubiquitin system for drug development [J]. Cell Res, 2016, 26: 484-498.
3
Sogbein O, Paul P, Umar M, et al. Bortezomib in cancer therapy: Mechanisms, side effects, and future proteasome inhibitors [J]. Life Sci, 2024, 358: 123125.
4
Zhang C, Liu YB, Li GC, et al. Targeting the undruggables-the power of protein degraders [J]. Sci Bull (Beijing), 2024, 69: 1776-1797.
5
Ciechanover A, Heller H, Elias S, et al. ATP-dependent conjugation of reticulocyte proteins with the polypeptide required for protein degradation [J]. Proc Natl Acad Sci U S A, 1980, 77: 1365-1368.
6
Hershko A, Ciechanover A, Heller H, et al. Proposed role of ATP in protein breakdown: Conjugation of proteins with multiple chains of the polypeptide of ATP-dependent proteolysis [J]. Proc Natl Acad Sci U S A, 1980, 77: 1783-1786.
7
Sakamoto KM, Kim KB, Kumagai A, et al. Protacs: Chimeric molecules that target proteins to the Skp1-Cullin-F box complex for ubiquitination and degradation [J]. Proc Natl Acad Sci U S A, 2001, 98: 8554-8559.
8
Schreiber SL. The rise of molecular glues [J]. Cell, 2021, 184: 3-9.
9
Banik SM, Pedram K, Wisnovsky S, et al. Lysosome-targeting chimaeras for degradation of extracellular proteins [J]. Nature, 2020, 584: 291-297.
10
Schapira M, Calabrese MF, Bullock AN, et al. Targeted protein degradation: Expanding the toolbox [J]. Nat Rev Drug Discov, 2019, 18: 949-963.
11
Chamberlain PP, Hamann LG. Development of targeted protein degradation therapeutics [J]. Nat Chem Biol, 2019, 15: 937-944.
12
Liu JH, Chen YM, Cai XQ. Research advances in new technologies in targeted protein degradation [J]. Acta Pharm Sin (药学学报), 2022, 57: 313-320.
13
Johnson DS, Weerapana E, Cravatt BF. Strategies for discovering and derisking covalent, irreversible enzyme inhibitors [J]. Future Med Chem, 2010, 2: 949-964.
14
Zeng SX, Huang WH, Zheng XL, et al. Proteolysis targeting chimera (PROTAC) in drug discovery paradigm: Recent progress and future challenges [J]. Eur J Med Chem, 2021, 210: 112981.
15
Yang YQ, Gao HY, Sun XY, et al. Global PROTAC toolbox for degrading BCR-ABL overcomes drug-resistant mutants and adverse effects [J]. J Med Chem, 2020, 63: 8567-8583.
16
Wu JJ, Hu JP. Pharmacokinetics of PROTACs and their research progress in disease treatment [J]. Acta Pharm Sin (药学学报), 2024, 59: 2484-2490.
17
Wilkinson KD. The discovery of ubiquitin-dependent proteolysis [J]. Proc Natl Acad Sci U S A, 2005, 102: 15280-15282.
18
Tooze SA, Dikic I. Autophagy captures the nobel prize [J]. Cell, 2016, 167: 1433-1435.
19
Pohl C, Dikic I. Cellular quality control by the ubiquitin-proteasome system and autophagy [J]. Science, 2019, 366: 818-822.
20
Qin H, Zhang YW, Lou YT, et al. Overview of PROTACs targeting the estrogen receptor: Achievements for biological and drug discovery [J]. Curr Med Chem, 2022, 29: 3922-3944.
21
Salvaris RT, Brennan J, Lewis KL. BTK is the target that keeps on giving: A review of BTK-degrader drug development, clinical data, and future directions in CLL [J]. Cancers (Basel), 2025, 17: 557.
22
Ackerman L, Acloque G, Bacchelli S, et al. IRAK4 degrader in hidradenitis suppurativa and atopic dermatitis: A phase 1 trial [J]. Nat Med, 2023, 29: 3127-3136.
23
Hinova Pharmaceuticals Inc. A phase Ⅰ/Ⅱ trial to evaluate oral HP568 tablets in patients with ER+/HER2 advanced breast cancer [EB/OL]. (2025-01-03) [2025-05-26]. https://clinicaltrials.gov/study/NCT06757335?term=T06757335&rank=1.
24
Haisco Pharmaceutical Group Co., Ltd. Phase I study of HSK40118 in NSCLC patients with EGFR mutation [EB/OL]. (2023-09-22) [2025-05-26]. https://clinicaltrials.gov/study/NCT06050980#study-overviews.
25
Krönke J, Udeshi N, Narla A, et al. Lenalidomide promotes CRBN-mediated ubiquitination and degradation of IKZF1 and IKZF3 [J]. Blood, 2013, 122: LBA-5.
26
Takahashi D, Moriyama J, Nakamura T, et al. AUTACs: Cargo-specific degraders using selective autophagy [J]. Mol Cell, 2019, 76: 797-810. e 710.
27
Li ZY, Zhu CG, Ding Y, et al. ATTEC: A potential new approach to target proteinopathies [J]. Autophagy, 2019, 16: 185-187.
28
Schiedel M, Herp D, Hammelmann S, et al. Chemically induced degradation of sirtuin 2 (Sirt2) by a proteolysis targeting chimera (PROTAC) based on sirtuin rearranging ligands (SirReals) [J]. J Med Chem, 2017, 61: 482-491.
29
Peng ZQ, Fang W, Wu B, et al. Targeting Smurf1 to block PDK1-Akt signaling in KRAS-mutated colorectal cancer [J]. Nat Chem Biol, 2024, 21: 59-70.
30
Teng XC, Zhao X, Dai YC, et al. ClickRNA-PROTAC for tumor-selective protein degradation and targeted cancer therapy [J]. J Am Chem Soc, 2024, 146: 27382-27391.
31
Mou Y, Wen S, Wang Y, et al. Research progress in controllable proteolysis targeting chimeras [J]. Acta Pharm Sin (药学学报), 2023, 58: 2193-2202.
32
Bauer D, Sarrett SM, Lewis JS, et al. Click chemistry: A transformative technology in nuclear medicine [J]. Nat Protoc, 2023, 18: 1659-1668.
33
Sletten EM, Bertozzi CR. From mechanism to mouse: A tale of two bioorthogonal reactions [J]. Acc Chem Res, 2011, 44: 666-676.
34
Agard NJ, Prescher JA, Bertozzi CR. A strain-promoted [3+2] azide-alkyne cycloaddition for covalent modification of biomolecules in living systems [J]. J Am Chem Soc, 2004, 126: 15046-15047.
35
Scinto SL, Bilodeau DA, Hincapie R, et al. Bioorthogonal chemistry [J]. Nat Rev Methods Primers, 2021, 1: 30.
36
Kim E, Koo H. Biomedical applications of copper-free click chemistry: In vitro, in vivo, and ex vivo [J]. Chem Sci, 2019, 10: 7835-7851.
37
Oliveira BL, Guo Z, Bernardes GJL. Inverse electron demand Diels-Alder reactions in chemical biology [J]. Chem Soc Rev, 2017, 46: 4895-4950.
38
He XY, Li J, Liang XX, et al. An all-in-one tetrazine reagent for cysteine-selective labeling and bioorthogonal activable prodrug construction [J]. Nat Commun, 2024, 15: 2831.
39
Deng YQ, Shen TR, Yu XY, et al. Tetrazine‐isonitrile bioorthogonal fluorogenic reactions enable multiplex labeling and wash-free bioimaging of live cells [J]. Angew Chem Int Ed Engl, 2024, 63: e202319853.
40
Tu JL, Xu MH, Parvez S, et al. Bioorthogonal removal of 3-isocyanopropyl groups enables the controlled release of fluorophores and drugs in vivo [J]. J Am Chem Soc, 2018, 140: 8410-8414.
41
Lebraud H, Wright DJ, Johnson CN, et al. Protein degradation by in-cell self-assembly of proteolysis targeting chimeras [J]. ACS Cent Sci, 2016, 2: 927-934.
42
Wurz RP, Dellamaggiore K, Dou H, et al. A "click chemistry platform" for the rapid synthesis of bispecific molecules for inducing protein degradation [J]. J Med Chem, 2017, 61: 453-461.
43
Chang MY, Gao F, Pontigon D, et al. Bioorthogonal PROTAC prodrugs enabled by on-target activation [J]. J Am Chem Soc, 2023, 145: 14155-14163.
44
Gao J, Hou B, Zhu Q, et al. Engineered bioorthogonal POLY-PROTAC nanoparticles for tumour-specific protein degradation and precise cancer therapy [J]. Nat Commun, 2022, 13: 4318.
45
Jin YH, Fan J, Wang RY, et al. Ligation to scavenging strategy enables on-demand termination of targeted protein degradation [J]. J Am Chem Soc, 2023, 145: 7218-7229.
46
Xie SW, Zhu JJ, Peng YH, et al. In vivo self-assembly of PROTACs by bioorthogonal chemistry for precision cancer therapy [J]. Angew Chem Int Ed Engl, 2025, 64: e202421713.
47
Xiong Y, Zhong Y, Yim H, et al. Bridged proteolysis targeting chimera (PROTAC) enables degradation of undruggable targets [J]. J Am Chem Soc, 2022, 144: 22622-22632.
48
Yang ZH, Chen M, Ge RX, et al. Identification of a non-inhibitory aptameric ligand to CRL2ZYG11B E3 ligase for targeted protein degradation [J]. Nat Commun, 2025, 16: 2494.
49
Yan XJ, Li Y, Wang GB, et al. Molecular basis for recognition of Gly/N-degrons by CRL2ZYG11B and CRL2ZER1 [J]. Mol Cell, 2021, 81: 3262-3274.e 3263.
50
Yang FF, Luo QH, Wang YC, et al. Targeted biomolecule regulation platform: A split-and-mix PROTAC approach [J]. J Am Chem Soc, 2023, 145: 7879-7887.
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doi: 10.16438/j.0513-4870.2025-0597
  • 接收时间：2025-05-26
  • 首发时间：2026-09-21
  • 出版时间：2026-05-12
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  • 收稿日期：2025-05-26
  • 修回日期：2025-07-27
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    1四川大学华西医院磁共振研究中心, 放射影像研究所, 四川 成都 610041
    2四川大学华西医院天然与仿生药物研究中心, 四川 成都 610041

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Percentage of total
species (%)
鹅膏菌科Amanitaceae 2 11 5.26 鹅膏菌属 Amanita 10 4.78
小菇科 Mycenaceae 2 12 5.74 丝盖伞属 Inocybe 5 2.39
多孔菌科 Polyporaceae 8 14 6.70 蜡蘑属 Laccaria 5 2.39
红菇科 Russulaceae 3 23 11.00 小皮伞属 Marasmius 6 2.87
小菇属 Mycena 11 5.26
光柄菇属 Pluteus 5 2.39
红菇属 Russula 17 8.13
栓菌属 Trametes 5 2.39
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