药学学报

Type	Target	Application scenario	Nucleic acid element	Synthesis technology	Key feature
TF-PROTAC	NF-κB/P65	Liver cancer	NF-κB binding sequence; DNA duplex	BCN-azide click chemistry	Blocks IL6/STAT3 inflammatory signaling
	Brachyury	Notochord development regulation	Brachyury binding sequence	Covalent conjugation with Cas9 CRISPR guide RNA	CRISPR-dCas9 targeted; embryonic validation
	STAT3	Diffuse large B-cell lymphoma	STAT3 binding sequence; DNA duplex	DBCO-azide click chemistry	Immune-cell delivery; overcomes tumor barriers
	LEF1	Prostate cancer	LEF1 binding sequence; DNA duplex	Phosphoramidite monomer; solid-phase synthesis	Inhibits β-catenin/LEF1 signaling
	ERG	Prostate cancer	ERG binding sequence; DNA duplex	Phosphoramidite monomer; solid-phase synthesis	Blocks EMT
	c-Myc/Max	Triple-negative breast cancer	TNA aptamer-E-box chimera	TNA-DNA bivalent linkage	Degrades c-Myc/Max heterodimer
	Nrf2-MafG	Non-small cell lung cancer	Nrf2-MafG binding sequence; DNA duplex	Alkyne-azide click chemistry	Degrades Nrf2-MafG heterodimer
Aptamer-PROTACs	BET	Breast cancer	AS1411 aptamer	Amide bond formation	Enhances tumor targeting
	Nucleolin	Breast cancer	AS1411 aptamer	DBCO-azide click chemistry	Tumor-selective uptake; reduced toxicity
		Breast cancer	AS1411 aptamer	Alkyne-azide click chemistry	Tumor-specific; photo-activatable
	BRD4	Liver cancer; melanoma	High-affinity aptamer (bead-selected)	Bead display-FACS functional screening platform	Function-driven screening
	p53-R175H mutant	Lung cancer	Mutant conformation-specific RNA aptamer	Alkyne-azide click chemistry	Mutant-specific targeting
	ERα	Hormone-dependent breast cancer	ER dimerization interface aptamer	Solid-phase synthesis with photocleavable linker	Spares DNA-binding domain
	c-MET	Osteosarcoma	c-MET specific aptamer	Complementary pairing of dual aptamers	Degrades oncogenic pathways; reverses resistance
RNA-PROTAC	Lin28A	Cancer cells	Lin28A ZKD-targeting sequence	Maleimide-SH conjugation	First RBP degrader
	RBFOX1	Neurons; breast cancer cells	RBFOX1 RNA recognition motif	Maleimide-SH conjugation	Selective splicing factor degradation
	Lin28A	Breast cancer	pre-let-7 miRNA mimic	Amide bond formation	Dual action: degrades Lin28A & restores let-7 maturation
G4-PROTAC	RHAU/DHX36	Cancer cells	DHX36-targeting DNA G-quadruplex	Alkyne-azide click chemistry	Validates G4-PROTAC concept
	DHX36	Gene regulation; muscle regeneration	DHX36-targeting RNA G-quadruplex	Alkyne-azide click chemistry	Inhibits muscle stem cell proliferation
	FMRP	Tumor immunotherapy	FMRP-targeting RNA G-quadruplex	DBCO-azide click chemistry	Reprograms tumor microenvironment
TeloTAC	TRF1/2	Telomere-related cancers	Telomeric repeat sequence (TTAGGG)	BCN-azide click chemistry	Induces telomere shortening
Methyl-PROTAC	MeCP2	Epigenetic regulation	Methylated DNA	BCN-azide click chemistry	Selectively kills MeCP2-overexpressing cancer cells

Type

Target

Application scenario

Nucleic acid element

Synthesis technology

Key feature

TF-PROTAC

NF-κB/P65

Liver cancer

NF-κB binding sequence; DNA duplex

BCN-azide click chemistry

Blocks IL6/STAT3 inflammatory signaling

Brachyury

Notochord development regulation

Brachyury binding sequence

Covalent conjugation with Cas9 CRISPR guide RNA

CRISPR-dCas9 targeted; embryonic validation

STAT3

Diffuse large B-cell lymphoma

STAT3 binding sequence; DNA duplex

DBCO-azide click chemistry

Immune-cell delivery; overcomes tumor barriers

LEF1

Prostate cancer

LEF1 binding sequence; DNA duplex

Phosphoramidite monomer; solid-phase synthesis

Inhibits β-catenin/LEF1 signaling

ERG

Prostate cancer

ERG binding sequence; DNA duplex

Phosphoramidite monomer; solid-phase synthesis

Blocks EMT

c-Myc/Max

Triple-negative breast cancer

TNA aptamer-E-box chimera

TNA-DNA bivalent linkage

Degrades c-Myc/Max heterodimer

Nrf2-MafG

Non-small cell lung cancer

Nrf2-MafG binding sequence; DNA duplex

Alkyne-azide click chemistry

Degrades Nrf2-MafG heterodimer

Aptamer-PROTACs

BET

Breast cancer

AS1411 aptamer

Amide bond formation

Enhances tumor targeting

Nucleolin

Breast cancer

AS1411 aptamer

DBCO-azide click chemistry

Tumor-selective uptake; reduced toxicity

Breast cancer

AS1411 aptamer

Alkyne-azide click chemistry

Tumor-specific; photo-activatable

BRD4

Liver cancer; melanoma

High-affinity aptamer (bead-selected)

Bead display-FACS functional screening platform

Function-driven screening

p53-R175H mutant

Lung cancer

Mutant conformation-specific RNA aptamer

Alkyne-azide click chemistry

Mutant-specific targeting

ERα

Hormone-dependent breast cancer

ER dimerization interface aptamer

Solid-phase synthesis with photocleavable linker

Spares DNA-binding domain

c-MET

Osteosarcoma

c-MET specific aptamer

Complementary pairing of dual aptamers

Degrades oncogenic pathways; reverses resistance

RNA-PROTAC

Lin28A

Cancer cells

Lin28A ZKD-targeting sequence

Maleimide-SH conjugation

First RBP degrader

RBFOX1

Neurons; breast cancer cells

RBFOX1 RNA recognition motif

Maleimide-SH conjugation

Selective splicing factor degradation

Lin28A

Breast cancer

pre-let-7 miRNA mimic

Amide bond formation

Dual action: degrades Lin28A & restores let-7 maturation

G4-PROTAC

RHAU/DHX36

Cancer cells

DHX36-targeting DNA G-quadruplex

Alkyne-azide click chemistry

Validates G4-PROTAC concept

DHX36

Gene regulation; muscle regeneration

DHX36-targeting RNA G-quadruplex

Alkyne-azide click chemistry

Inhibits muscle stem cell proliferation

FMRP

Tumor immunotherapy

FMRP-targeting RNA G-quadruplex

DBCO-azide click chemistry

Reprograms tumor microenvironment

TeloTAC

TRF1/2

Telomere-related cancers

Telomeric repeat sequence (TTAGGG)

BCN-azide click chemistry

Induces telomere shortening

Methyl-PROTAC

MeCP2

Epigenetic regulation

Methylated DNA

BCN-azide click chemistry

Selectively kills MeCP2-overexpressing cancer cells

Type	Target	Application scenario	Nucleic acid element	Synthesis technology	Key feature
TF-PROTAC	NF-κB/P65	Liver cancer	NF-κB binding sequence; DNA duplex	BCN-azide click chemistry	Blocks IL6/STAT3 inflammatory signaling
	Brachyury	Notochord development regulation	Brachyury binding sequence	Covalent conjugation with Cas9 CRISPR guide RNA	CRISPR-dCas9 targeted; embryonic validation
	STAT3	Diffuse large B-cell lymphoma	STAT3 binding sequence; DNA duplex	DBCO-azide click chemistry	Immune-cell delivery; overcomes tumor barriers
	LEF1	Prostate cancer	LEF1 binding sequence; DNA duplex	Phosphoramidite monomer; solid-phase synthesis	Inhibits β-catenin/LEF1 signaling
	ERG	Prostate cancer	ERG binding sequence; DNA duplex	Phosphoramidite monomer; solid-phase synthesis	Blocks EMT
	c-Myc/Max	Triple-negative breast cancer	TNA aptamer-E-box chimera	TNA-DNA bivalent linkage	Degrades c-Myc/Max heterodimer
	Nrf2-MafG	Non-small cell lung cancer	Nrf2-MafG binding sequence; DNA duplex	Alkyne-azide click chemistry	Degrades Nrf2-MafG heterodimer
Aptamer-PROTACs	BET	Breast cancer	AS1411 aptamer	Amide bond formation	Enhances tumor targeting
	Nucleolin	Breast cancer	AS1411 aptamer	DBCO-azide click chemistry	Tumor-selective uptake; reduced toxicity
		Breast cancer	AS1411 aptamer	Alkyne-azide click chemistry	Tumor-specific; photo-activatable
	BRD4	Liver cancer; melanoma	High-affinity aptamer (bead-selected)	Bead display-FACS functional screening platform	Function-driven screening
	p53-R175H mutant	Lung cancer	Mutant conformation-specific RNA aptamer	Alkyne-azide click chemistry	Mutant-specific targeting
	ERα	Hormone-dependent breast cancer	ER dimerization interface aptamer	Solid-phase synthesis with photocleavable linker	Spares DNA-binding domain
	c-MET	Osteosarcoma	c-MET specific aptamer	Complementary pairing of dual aptamers	Degrades oncogenic pathways; reverses resistance
RNA-PROTAC	Lin28A	Cancer cells	Lin28A ZKD-targeting sequence	Maleimide-SH conjugation	First RBP degrader
	RBFOX1	Neurons; breast cancer cells	RBFOX1 RNA recognition motif	Maleimide-SH conjugation	Selective splicing factor degradation
	Lin28A	Breast cancer	pre-let-7 miRNA mimic	Amide bond formation	Dual action: degrades Lin28A & restores let-7 maturation
G4-PROTAC	RHAU/DHX36	Cancer cells	DHX36-targeting DNA G-quadruplex	Alkyne-azide click chemistry	Validates G4-PROTAC concept
	DHX36	Gene regulation; muscle regeneration	DHX36-targeting RNA G-quadruplex	Alkyne-azide click chemistry	Inhibits muscle stem cell proliferation
	FMRP	Tumor immunotherapy	FMRP-targeting RNA G-quadruplex	DBCO-azide click chemistry	Reprograms tumor microenvironment
TeloTAC	TRF1/2	Telomere-related cancers	Telomeric repeat sequence (TTAGGG)	BCN-azide click chemistry	Induces telomere shortening
Methyl-PROTAC	MeCP2	Epigenetic regulation	Methylated DNA	BCN-azide click chemistry	Selectively kills MeCP2-overexpressing cancer cells

Type

Target

Application scenario

Nucleic acid element

Synthesis technology

Key feature

TF-PROTAC

NF-κB/P65

Liver cancer

NF-κB binding sequence; DNA duplex

BCN-azide click chemistry

Blocks IL6/STAT3 inflammatory signaling

Brachyury

Notochord development regulation

Brachyury binding sequence

Covalent conjugation with Cas9 CRISPR guide RNA

CRISPR-dCas9 targeted; embryonic validation

STAT3

Diffuse large B-cell lymphoma

STAT3 binding sequence; DNA duplex

DBCO-azide click chemistry

Immune-cell delivery; overcomes tumor barriers

LEF1

Prostate cancer

LEF1 binding sequence; DNA duplex

Phosphoramidite monomer; solid-phase synthesis

Inhibits β-catenin/LEF1 signaling

ERG

Prostate cancer

ERG binding sequence; DNA duplex

Phosphoramidite monomer; solid-phase synthesis

Blocks EMT

c-Myc/Max

Triple-negative breast cancer

TNA aptamer-E-box chimera

TNA-DNA bivalent linkage

Degrades c-Myc/Max heterodimer

Nrf2-MafG

Non-small cell lung cancer

Nrf2-MafG binding sequence; DNA duplex

Alkyne-azide click chemistry

Degrades Nrf2-MafG heterodimer

Aptamer-PROTACs

BET

Breast cancer

AS1411 aptamer

Amide bond formation

Enhances tumor targeting

Nucleolin

Breast cancer

AS1411 aptamer

DBCO-azide click chemistry

Tumor-selective uptake; reduced toxicity

Breast cancer

AS1411 aptamer

Alkyne-azide click chemistry

Tumor-specific; photo-activatable

BRD4

Liver cancer; melanoma

High-affinity aptamer (bead-selected)

Bead display-FACS functional screening platform

Function-driven screening

p53-R175H mutant

Lung cancer

Mutant conformation-specific RNA aptamer

Alkyne-azide click chemistry

Mutant-specific targeting

ERα

Hormone-dependent breast cancer

ER dimerization interface aptamer

Solid-phase synthesis with photocleavable linker

Spares DNA-binding domain

c-MET

Osteosarcoma

c-MET specific aptamer

Complementary pairing of dual aptamers

Degrades oncogenic pathways; reverses resistance

RNA-PROTAC

Lin28A

Cancer cells

Lin28A ZKD-targeting sequence

Maleimide-SH conjugation

First RBP degrader

RBFOX1

Neurons; breast cancer cells

RBFOX1 RNA recognition motif

Maleimide-SH conjugation

Selective splicing factor degradation

Lin28A

Breast cancer

pre-let-7 miRNA mimic

Amide bond formation

Dual action: degrades Lin28A & restores let-7 maturation

G4-PROTAC

RHAU/DHX36

Cancer cells

DHX36-targeting DNA G-quadruplex

Alkyne-azide click chemistry

Validates G4-PROTAC concept

DHX36

Gene regulation; muscle regeneration

DHX36-targeting RNA G-quadruplex

Alkyne-azide click chemistry

Inhibits muscle stem cell proliferation

FMRP

Tumor immunotherapy

FMRP-targeting RNA G-quadruplex

DBCO-azide click chemistry

Reprograms tumor microenvironment

TeloTAC

TRF1/2

Telomere-related cancers

Telomeric repeat sequence (TTAGGG)

BCN-azide click chemistry

Induces telomere shortening

Methyl-PROTAC

MeCP2

Epigenetic regulation

Methylated DNA

BCN-azide click chemistry

Selectively kills MeCP2-overexpressing cancer cells

基于核酸的PROTAC技术: 新兴策略与未来展望

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许建飞 , 闫兆鹏 , 郭东阳 , 王倩 , 王静 , 汤新景 ^*

药学学报 | 专题报道: 靶向蛋白降解药物前沿进展评述 2025,60(11): 3283-3296

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药学学报 |专题报道: 靶向蛋白降解药物前沿进展评述 2025 , 60 (11) : 3283 -3296

基于核酸的PROTAC技术: 新兴策略与未来展望

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许建飞, 闫兆鹏, 郭东阳, 王倩, 王静, 汤新景^*

作者信息

北京大学药学院, 天然药物及仿生药物全国重点实验室和化学生物学中心, 北京 100191

通讯作者:

汤新景, Tel: 86-10-82805635, E-mail: xinjingt@bjmu.edu.cn

作者简介:

^#共同第一作者.

作者贡献:

许建飞和闫兆鹏负责论文初稿的撰写; 郭东阳负责图表绘制与修改; 王倩和王静对论文进行了修改; 汤新景对论文质量进行指导, 修改和定稿。

Nucleic acid-based PROTACs: emerging strategies and future perspectives

Jian-fei XU, Zhao-peng YAN, Dong-yang GUO, Qian WANG, Jing WANG, Xin-jing TANG^*

Affiliations

State Key Laboratory of Natural and Biomimetic Drugs, Chemical Biology Center and School of Pharmaceutical Sciences, Peking University, Beijing 100191, China

出版时间: 2025-11-12 doi: 10.16438/j.0513-4870.2025-0456

文章导航

摘要

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靶向蛋白降解技术(targeted protein degradation, TPD) 通过泛素-蛋白酶体系统(ubiquitin-proteasome system, UPS) 或溶酶体途径实现目标蛋白的特异性降解。作为该领域的突破性策略, 蛋白降解靶向嵌合体(proteolysis-targeting chimeras, PROTACs) 因其独特的催化性降解机制、靶向“不可成药蛋白”的能力、克服耐药性的潜力及高度选择性, 已成为创新药物研发的重要方向。然而, 对于缺乏明确结合位点的蛋白, 如转录因子(transcription factors, TFs) 和RNA结合蛋白(RNA-binding proteins, RBPs) 等, 依赖靶蛋白配体的传统小分子PROTACs降解靶蛋白的效果不佳。基于此, 以寡核苷酸为靶向元件的PROTAC技术应运而生, 其通过核酸序列特异性识别靶标, 显著拓展了可降解蛋白的范围。本文系统综述了寡核苷酸-PROTAC技术的前沿进展, 涵盖靶向转录因子降解嵌合体(TF-PROTACs)、RNA靶向蛋白嵌合体(RNA-PROTACs)、G四链体靶向蛋白降解嵌合体(G4-PROTACs) 和核酸适配体靶向蛋白降解嵌合体(aptamer-PROTACs) 等创新设计策略及其在疾病治疗中的应用前景, 并探讨其面临的稳定性、递送效率等挑战及未来发展方向。通过整合核酸分子生物学与蛋白降解技术, 这一交叉学科策略有望为靶向“不可成药”蛋白及难治性疾病治疗开辟全新的药物研发策略。

关键词

蛋白降解靶向嵌合体 / 嵌合核酸 / 转录因子 / RNA结合蛋白 / 不可成药蛋白

Abstract

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Targeted protein degradation (TPD) technology achieves selective degradation of target proteins through the ubiquitin-proteasome system (UPS) or lysosomal pathways. Among TPD strategies, proteolysis-targeting chimeras (PROTACs) have emerged as a transformative approach in innovative drug discovery, offering unique advantages such as the ability to target "undruggable" proteins, catalytic degradation kinetics, potential to circumvent drug resistance, and high selectivity. However, conventional small-molecule PROTACs depend on ligands binding to target proteins, limiting their effectiveness against molecules without well-defined binding sites, such as transcription factors (TFs) and RNA-binding proteins (RBPs). To overcome this limitation, oligonucleotide-based PROTAC technology has been developed, utilizing sequence-specific nucleic acid recognition to significantly expand the repertoire of degradable targets. This review systematically summarizes recent advances in oligonucleotide-PROTACs, including innovative designs like TF-PROTACs, RNA-PROTACs, G4-PROTACs, and aptamer-PROTACs, along with their therapeutic potentials. We further discuss persisting challenges such as molecular stability and delivery efficiency, and propose future directions for the field. By integrating nucleic acid molecular biology with protein degradation technologies, this interdisciplinary paradigm promises to unlock novel therapeutic strategies for "undruggable" targets and previously intractable diseases.

Key words

PROTAC / chimeric oligonucleotide / transcription factor / RNA-binding protein / undruggable protein

引用本文

许建飞, 闫兆鹏, 郭东阳, 王倩, 王静, 汤新景. 基于核酸的PROTAC技术: 新兴策略与未来展望. 药学学报, 2025 , 60 (11) : 3283 -3296 . DOI: 10.16438/j.0513-4870.2025-0456

Jian-fei XU, Zhao-peng YAN, Dong-yang GUO, Qian WANG, Jing WANG, Xin-jing TANG. Nucleic acid-based PROTACs: emerging strategies and future perspectives[J]. Acta Pharmaceutica Sinica, 2025 , 60 (11) : 3283 -3296 . DOI: 10.16438/j.0513-4870.2025-0456

正文

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靶向蛋白降解技术(targeted protein degradation, TPD) 通过劫持细胞内天然降解机制——泛素-蛋白酶体系统(ubiquitin-proteasome system, UPS)^[1,2]或溶酶体途径^[3]实现对致病蛋白的特异性清除, 为传统“不可成药”靶点的干预提供了革命性工具^[4,5]。作为TPD的核心策略, 蛋白降解靶向嵌合体(proteolysis-targeting chimera, PROTAC) 通过异双功能分子桥接靶蛋白(protein of interest, POI) 与E3泛素连接酶, 形成三元复合物并诱导POI的泛素化标记及蛋白酶体降解^[6]。与传统小分子抑制剂的“占据驱动”模式不同, PROTAC遵循“事件驱动”^[1,7]机制, 其催化循环特性允许单分子介导多轮靶蛋白降解, 显著降低有效剂量需求^[8]。

自2001年Craig Crews团队^[9]开创性提出蛋白降解靶向嵌合体概念以来, 该技术经历了从多肽到小分子配体的迭代发展, 逐步建立起以VHL、CRBN、MDM2和IAP4大E3连接酶为核心的降解体系^[6,10-14]。迄今为止, 已开发出可诱导130多种目标蛋白降解的PROTAC分子, 涵盖癌症、免疫疾病、病毒感染和神经退行性疾病等多个病症^[15,16]。自2013年起, 默克、诺华、辉瑞等药企巨头及专注于PROTAC研发的Arvinas和C4治疗公司等生物技术公司, 均积极布局PROTAC管线。Arvinas公司开发的ARV-110和ARV-471分别用于治疗转移性去势抵抗性前列腺癌和ER⁺/HER2^-乳腺癌^[17-19], 并在临床试验中展现出良好的安全性与耐受性, 为PROTAC技术在肿瘤治疗领域的临床应用提供了有力证据。其中, ARV-110已进入Ⅱ期临床试验, ARV-471更是推进至Ⅲ期, 并正在探索与其他抗癌疗法的联合应用。此外, 2021年FDA批准了DT2216 (NCT0488662) 用于治疗晚期血液瘤和实体肿瘤的Ⅰ期临床研究^[20]。此外, 靶向细胞介素-1受体相关激酶4 (interleukin-1 receptor-associated kinase 4, IRAK4)、信号转与转录激活子3 (signal transducer and activator of transcription 3, STAT3) 和布鲁顿酪氨酸蛋白激酶(Bruton's tyrosine kinase, BTK) 等蛋白降解剂, 如KT-413 (IRAK4)、KT-333 (STAT3) 和NX-5948 (BTK), 也已相继进入临床试验阶段^[20]。这些积极的临床数据标志着PROTAC技术向新型治疗策略转变的重要里程碑。然而, 传统PROTAC的开发仍面临显著的靶点选择偏倚问题, 人类疾病相关蛋白靶点中超过80%属于缺乏明确结合口袋的“不可成药”蛋白, 包括转录因子、RNA结合蛋白及支架蛋白等^[21-28]。例如，转录因子STAT3的DNA结合域呈扁平构型, 传统小分子抑制剂策略难以有效靶向这类结合界面。近年来, 尽管新型E3连接酶配体的开发为靶点扩展提供了新方向, 但PROTAC-DB数据库显示, 已报道的PROTAC分子中仍有90%依赖VHL或CRBN配体, 这种E3连接酶的单一化倾向可能加剧临床耐药风险^[29]。上述结构生物学特征与化学空间限制共同构成了传统PROTAC突破“可成药性”边界的根本性障碍^[30]。

基于核酸的PROTAC技术通过整合寡核苷酸的序列特异性识别能力与模块化设计, 突破了传统小分子降解剂在靶标选择性和分子设计上的多重限制^[31-33]。该技术利用核酸分子作为精准靶向元件, 通过碱基互补配对或特异性空间构象识别靶蛋白的关键功能域^[34,35]。例如, DNA双链可精确匹配转录因子NF-κB的DNA结合基序(5′-GGGAATTTCC-3′), 而核酸适配体AS1411通过其独特的四链体结构以纳摩尔级亲和力结合核仁素, 其靶向效率显著优于传统抗体。通过点击化学、固相合成或酶催化连接技术, 将E3连接酶配体共价偶联至核酸骨架的特定位点, 构建具有异双功能特性的嵌合体分子^[36-38]。这种设计策略不仅克服了小分子配体在结合界面深度和空间位阻上的局限性, 还可通过碱基突变或二级结构优化灵活调节靶标特异性, 如通过系统演化平台迭代优化适配体序列与E3配体的空间排布, 实现三元复合物形成效率的精准调控^[39,40]。此外, 核酸模块的化学修饰(如2′-氟代、硫代磷酸酯、锁核酸) 显著提升了体内稳定性, 其血浆半衰期延长至48 h以上, 而模块化设计使得单次给药即可实现持续数天的靶蛋白抑制效果^[37,41,42]。

目前, 基于核酸的蛋白靶向降解策略主要通过溶酶体途径和泛素-蛋白酶体途径实现。溶酶体途径主要是利用核酸适配体作为靶向模块, 连接靶蛋白和细胞表面的溶酶体穿梭受体, 引导靶蛋白进入溶酶体降解, 如适配体-LYTACs (lysosome-targeting chimaeras, LYTACs)^[43]、双特异性适配体嵌合体^[44]、靶向整合素适配体介导的嵌合体^[45]、多价适配体-LYTACs^[46]及共价适配体嵌合体^[47-49]。相比之下, 基于泛素-蛋白酶体途径的核酸-PROTAC策略则利用核酸分子作为靶向模块连接靶蛋白和E3泛素连接酶, 诱导靶蛋白泛素化并被蛋白酶体降解, 是基于核酸的靶向蛋白降解的主流方向。本文将主要系统阐述针对不同类型靶标蛋白靶向降解的各类核酸-PROTAC策略的最新研究进展。

1　基于核酸的PROTAC技术研究进展

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目前, 研究者已开发出多样化的核酸-PROTAC策略以靶向不同功能类别的蛋白靶点, 包括转录因子^{[27,33,35,50,51]}、RNA结合蛋白^{[27,35,50,52-54]}、特定核酸结构结合蛋白^[33,55-58]等。而作为核酸-PROTAC的核酸配体则包括各种可以与待降解蛋白结合的功能核酸, 例如结合转录因子的DNA双链、靶向RNA结合蛋白的miRNA, 以及G四链体和多种不同的核酸适配体等。本文将系统阐述这些核酸-PROTAC策略的设计原理、分子机制及在多种疾病模型中的治疗潜力。

1.1　转录因子靶向降解嵌合体

转录因子(transcription factor, TF) 作为一类关键的DNA结合蛋白, 通过调控基因转录在胚胎发育、细胞分化和肿瘤发生等生物过程中发挥着核心作用^[59]。据统计, 约20%的人类癌症由转录因子异常激活或突变驱动, 如c-Myc在60%以上的实体瘤中过表达, NF-κB通路在炎症相关肿瘤中持续活化。然而, 这类蛋白缺乏酶活性位点和配体结合口袋, 传统小分子药物难以直接干预其功能, 导致约80%的疾病相关转录因子长期被列为“不可成药”靶点^[60]。近年来, PROTAC技术的突破性发展为这一困境提供了新思路^[61-63]。传统小分子PROTAC已在雄激素受体(androgen receptor, AR) 和雌激素受体(estrogen receptor, ER) 等核受体转录因子的靶向降解中取得临床进展^[64,65]。但该策略对缺乏小分子配体的转录因子仍束手无策, 急需更具创新性的解决方案^[59,60]。目前已经开发出多种基于核酸的转录因子靶向降解嵌合体, 其作用靶点、应用场景、合成工艺和特点等信息列在表1中。

Crews课题组报道的转录因子靶向嵌合体(transcription factor targeting chimeras, TRAFTACs) 技术首次将CRISPR-dCas9系统^[66]与PROTAC原理结合^[67]。该降解剂采用NF-κB特异性DNA识别序列(5′-GGG AATTTCC-3′) 作为核酸靶向模块, 通过HaloTag7蛋白融合体作为连接桥接系统, 利用VHL-E3连接酶实现目标转录因子的特异性降解。在HEK293细胞模型中, 该技术可诱导NF-κB p50亚基在12 h内降解约80%。在斑马鱼胚胎模型中, 该技术成功降解脊索发育关键因子Brachyury, 显著降低胚胎发育畸形率(约70%的胚胎出现严重尾部缺陷, 而对照组仅 < 5%), 首次验证了核酸-PROTAC在活体系统中的可行性。进一步优化的OligoTRAFTACs^[68]通过硫代磷酸酯修饰的c-Myc E-box DNA序列(5′-CACGTG-3′) 作为核酸靶向元件, 通过CuAAC点击化学将BCN修饰的VHL配体(含5个乙二醇单元的PEG5连接子) 直接共价偶联至寡核苷酸末端, 实现了对c-Myc和脊索发育关键因子Brachyury的高效降解。针对c-Myc的降解剂(OT7) 在50 nmol·L^-1浓度下处理20 h可实现大于70%的蛋白清除率; 而针对Brachyury的PS修饰版本(OT17) 在15~30 nmol·L^-1浓度处理24 h后, 可在脊索瘤细胞中实现大于60%的内源性靶蛋白降解。该技术在斑马鱼胚胎模型中也证实了其强大的体内活性, 显微注射Brachyury靶向降解剂(OT17) 导致69%胚胎出现尾部畸形。通过优化连接子长度, 其降解效率可达亚微摩尔级别。值得注意的是, 该策略通过全基因组染色质免疫沉淀测序证实, 降解过程不会干扰靶蛋白在非病变区域的正常转录调控功能, 为治疗特异性提供了分子层面的保障。

固相合成和化学修饰提升了TF-PROTAC的稳定性和靶向精准性^[69]。Wei团队^[70]开发的TF-PROTACs采用硫代修饰NF-κB结合基序(5′-TGGGGACTTTCC-3′) 优化核酸序列, 设计并筛选了18种长烷基链/PEG连接臂, 并选用VHL配体(VH032) 招募E3泛素连接酶, 在肝癌模型中实现对p65蛋白的高效降解, 最佳降解剂dNF-κB#16在10 μg·mL^-1质量浓度下可使p65蛋白水平降低超过50%, 并通过阻断IL-6/STAT3信号轴抑制肿瘤增殖(图1)。Kortylewski团队^[71]采用双链发夹DNA诱饵序列(5′-CATTTCCCGTAAATC-3′) 靶向STAT3, 通过硫代磷酸酯修饰增强核酸稳定性, 结合单丙二醇连接子优化泛素化位点(K601/K626) 与E2催化中心的距离, 并选用沙利度胺招募CRBN E3连接酶, 开发了STAT3D-PROTAC。该嵌合核酸分子在弥漫大B细胞淋巴瘤(diffuse large B cell lymphoma, DLBCL) 细胞中降解STAT3, 在2 μmol·L^-1浓度下最大降解率可达85%, 并抑制下游BCL2L1和MYC基因表达。通过进一步与TLR9靶向CpG序列偶联, 实现选择性递送至淋巴瘤细胞, 在荷瘤小鼠模型中有效抑制肿瘤生长。该技术通过整合靶向递送与降解功能, 解决了转录因子抑制剂的脱靶毒性问题。更精巧的O'PROTACs技术将E3连接酶配体修饰为亚磷酰胺单体, 利用DNA合成仪实现自动化组装成功构建靶向前列腺癌相关因子LEF1 (DC₅₀ = 25 nmol·L^-1) 和ERG (DC₅₀ = 182.4 nmol·L^-1) 的降解剂^[72]。这种技术突破不仅解决了传统PROTAC连接子优化的经验依赖性问题, 还可通过碱基编辑快速调整靶标特异性, 为个性化治疗提供了技术储备。

针对转录因子二聚化特征设计的二价PROTAC展现出独特优势^[21,73]。通过将硫代修饰的TNA适配体与E-box DNA序列串联, 并通过采用NHS酯-酰胺键直接偶联泊马度胺至E-box序列的3′端, 构建的双价分子TEP可同时结合c-Myc/Max异源二聚体的两个亚基, 在Hs578T三阴性乳腺癌细胞中能有效降解内源性c-Myc/Max异源二聚体, 其DC₅₀约为53 nmol·L^-1, 并在处理10 h后达到最大降解程度。在三阴性乳腺癌模型中与CDK4/6抑制剂帕博西利联用, 具有显著的协同治疗效果^[74-77]。由于不同的转录因子可以识别并结合相似的DNA序列, 使用单个DNA寡核苷酸E-box序列作为靶向配体可能会导致非预期转录因子的序列依赖性脱靶降解, 将靶特异性TNA适体附加到E-box可以提高PROTAC平台的靶向特异性。Jiang团队^[22]针对抗氧化转录因子Nrf2-MafG异源二聚体, 设计了一种基于双链DNA的嵌合降解剂ARE-PROTACs C2, 成功诱导Nrf2-MafG复合体共降解。ARE-PROTACs通过直接截取靶基因启动子区的天然ARE序列(5′-TCACAGTGACTCAGCAGAATC-3′) 作为结合基序, 结合点击化学构建的多样化连接子库筛选合适连接臂, 并依据E3连接酶细胞表达谱选择CRBN配体。在非小细胞肺癌模型中, C2能高效诱导Nrf2-MafG复合体的共降解(对Nrf2的DC₅₀为1.85 nmol·L^-1, 对MafG的DC₅₀为66 nmol·L^-1), 其通过抑制Nrf2-ARE转录活性, 使谷胱甘肽水平下降, 并增强癌细胞对铁死亡诱导剂Erastin的敏感性, 也为靶向复合物依赖性转录调控提供了范例。

通过DNA双链等核酸分子特异性识别转录因子的DNA结合域^[78], 结合点击化学偶联E3连接酶配体及靶向递送, 实现了对众多转录因子高效降解。化学修饰和二价设计策略进一步提升了稳定性与协同效应^[25,79,80], 并通过多学科交叉(如CRISPR、光点击化学等) 加速了技术迭代与临床转化^[81,82]。这些创新策略通过精准的核酸序列识别与分子组装, 不仅拓展了转录因子靶向降解的技术维度, 更为解决“不可成药”靶点难题提供了精准的研究手段。

TF-PROTACs的核心优势在于利用特定双链核酸序列识别转录因子的DNA结合域。然而, 这种特异性识别也面临挑战。不同的转录因子家族成员(如AP-1家族中的c-Fos/c-Jun) 或其不同亚型可能识别高度相似甚至相同的DNA基序(如E-box)。使用单一的DNA寡核苷酸作为靶向元件可能导致非靶标但具有相似DNA结合特性的转录因子被意外招募和降解(脱靶效应)。例如, 靶向c-Myc/Max的E-box序列也可能被其他bHLH-Zip家族成员(如upstream stimulatory factor, USF) 识别^[83]。虽然采用双价设计(如结合适配体与E-box串联) 能在一定程度上提高对靶标的选择性, 但在基因组尺度上精确区分高度同源的转录因子结合位点仍是TF-PROTACs发展面临的关键挑战。

1.2　核酸适配体靶向蛋白降解嵌合体

相较于依赖DNA双链识别特定结构域(如DNA binding domain, DBD) 的TF-PROTACs, 核酸适配体(aptamer) 提供了更为灵活和通用的蛋白靶向解决方案。作为新一代分子识别元件, 其发展正推动着靶向蛋白降解技术的范式革新^[84,85]。这类通过体外筛选技术(如指数富集配体系统进化技术, systematic evolution of ligands by exponential enrichment, SELEX) 获得的单链DNA或RNA寡核苷酸, 通过构象折叠形成特异性三维结构, 能够以皮摩尔至纳摩尔级亲和力精准识别靶蛋白^[86], 兼具低免疫原性^[87]、易化学修饰^[88,89]及稳定性强^[90]等优势。与传统抗体相比, 适配体在分子质量、合成可控性及组织穿透性等方面展现出显著优势。核酸适配体具备的“化学抗体”特性使其在肿瘤靶向治疗中展现出独特潜力, 特别是在克服传统蛋白降解靶向嵌合体技术面临的靶点选择性不足和脱靶毒性问题上, 显现出更优越的解决方案。

近年来, 研究者通过将适配体的分子识别功能与PROTAC的催化降解机制创新性结合, 开发出多种兼具靶向特异性和高效降解能力的分子工具^[91,92](表1)。其中代表性的策略之一是构建适配体-药物偶联物(aptamer-drug conjugate, ADC)^[93-100]。以核仁素(nucleolin, NCL) 靶向适配体AS1411为例^[91], 其形成的G-四链体结构可特异性识别肿瘤细胞表面高表达的核仁素, 通过网格蛋白介导的内吞作用实现靶向递送。研究证实, 将AS1411与BET蛋白降解剂偶联构建的嵌合分子, 在肿瘤微环境中表现出显著增强的富集能力和持续降解效应。这种精准递送机制不仅提高了肿瘤选择性, 还通过减少系统暴露有效降低了传统PROTAC的剂量依赖性毒性, 为临床转化提供了重要的安全性保障^[101]。

核酸适配体在PROTAC设计中的创新应用还体现在其作为靶向配体的新策略。例如, Zhang等^[91]设计的ZL216分子以AS1411适配体(5′-GGTGGTGGT GGTTGTGGTGGTGGTGGT-3′) 作为靶向配体, 采用DBCO-azide点击化学构建稳定连接子, 并使用VHL配体作为E3连接酶招募单元, 实现了对NCL的肿瘤选择性降解。其在MCF-7和BT474乳腺癌细胞中表现出显著的降解效力, DC₅₀值分别为13.5和17.8 nmol·L^-1, 最大降解程度分别达到77%和87%。ZL216分子通过适配体介导的靶向内化, 在肿瘤细胞内形成稳定的三元复合物, 实现纳摩尔级的蛋白降解效力, 且对正常乳腺细胞无显著影响。类似地, Chen等^[93]利用靶向核仁素的AS1411适配体作为靶向模块, 通过点击化学反应将其与沙利度胺衍生物连接, 并以T碱基和PEG单元作为连接臂进行筛选优化, 其中, 含一个T碱基连接臂的dNCL#T1降解剂效果最优, 在0.5 μmol·L^-1浓度下处理24 h即可显著降解乳腺癌细胞MCF-7中约70%的NCL蛋白。在乳腺癌细胞中dNCL#T1通过泛素-蛋白酶体途径特异性降解NCL蛋白, 并高效抑制肿瘤细胞增殖与迁移(图2^[102])。此外, 通过引入光敏互补寡核苷酸, 作者构建了光控型opto-dNCL#T1, 其在未激活状态下保持惰性, 特定波长光照或肿瘤微环境刺激可诱导释放出活性的嵌合分子, 从而实现了dNCL#T1降解活性的时空精准调控, 为解决脱靶效应提供了创新思路。上述研究证实适配体不仅能维持与靶蛋白的结合能力, 还可通过合理设计的连接子维持PROTAC分子与E3连接酶的空间构象, 确保三元复合物的有效形成。

技术创新的最前沿体现在系统性进化平台的建立。Zhang团队^[102]近期开发的“微珠展示-功能筛选”系统, 推动了适配体-PROTAC技术的进步。通过构建大容量随机寡核苷酸库, 在微珠表面展示CRBN/VHL配体修饰的适配体嵌合体。采用双荧光标记策略(FITC标记泛素、APC标记靶蛋白) 结合FACS技术, 直接筛选能募集E3连接酶并诱导靶蛋白泛素化的功能性适配体。以BRD4为模型靶点, 经多轮筛选获得的PA2适配体在500 nmol·L^-1浓度下实现79.4%的BRD4降解(DC₅₀ = 199.9 nmol·L^-1), 并显著降低下游c-Myc蛋白表达水平。该团队进一步开发的双特异性RNA适配体降解剂, 通过同时结合BRD4和VHL E3连接酶复合体, 在纳摩尔浓度下实现近80%的BRD4降解。这种系统性进化策略的核心优势在于其“功能导向”筛选机制, 直接针对泛素化效率进行优化, 避免了传统“先亲和力后功能”的分步筛选缺陷。

在突变蛋白选择性降解方向, Meng团队^[103]研究发现, 特定RNA适配体可通过构象动态调整识别致癌突变体(如p53-R175H) 特有的表面拓扑特征。这种选择性源于适配体与突变体间形成的“锁-钥”式空间互补, 突变诱导的疏水腔隙为适配体结合提供特异性锚定位点, 而野生型蛋白因关键残基的空间位阻无法形成稳定复合物。该团队选用靶向p53-R175H突变体的RNA适配体(p53m-RA), 通过结构分析确认其特异性结合突变蛋白的L2-L3沟槽区域, 进而通过点击化学将CRBN配体直接连接至适配体5′端, 实现了对p53-R175H突变体的特异性降解(1 μmol·L^-1浓度下实现约80%的p53-R175H选择性降解), 同时完全保留野生型p53活性。上述构建的适配体-PROTAC嵌合分子竞争性抑制突变体与DNA元件的结合, 恢复肿瘤抑制通路的正常功能, 同时保持野生型蛋白活性完整, 为精准靶向致癌突变提供了分子基础。这种结合计算机辅助适配体设计策略(针对突变蛋白的特异构象进行理性设计), 显著增强了基于适配体的PROTAC分子在靶向降解中的特异性。

在核受体靶向治疗领域, 适配体-PROTAC展现出独特的分子识别优势。针对雌激素受体α (ERα) 开发的降解剂通过特异性结合受体二聚化界面, 在不干扰DNA结合域的情况下有效抑制转录活性。该团队采用已知ERα适配体ER (apt) D1 (5′-CCCGGCATGGTT GCGGAGCAGGAGTATAACACTACCATTG-3′) 作为靶向模块, 通过5′端炔基-PEG3-叠氮点击化学连接泊马度胺构建嵌合体, 其中POM-ER (apt) D1展现出最强降解效力, 在MCF-7细胞中200 nmol·L^-1浓度下降解率大于50%, 较VHL/cIAP配体高2.5倍。圆二色谱分析证实, 适配体与E3配体的偶联未改变其核心二级结构, 保证了靶标识别能力^[104]。此类嵌合分子涉及蛋白酶体依赖的降解途径和受体再合成抑制的双重调控, 对核受体家族成员表现出高度选择性, 为激素依赖性肿瘤治疗开辟了精准干预途径。

在骨肉瘤治疗领域, 适配体-PROTAC技术展现出突破性的靶向能力。研究者通过合理设计双适配体系统, 将核仁素靶向适配体与受体酪氨酸激酶c-MET特异性适配体进行偶联, 构建出具有协同效应的分子工具。构建的AS1411-SL1-2降解剂在MNNG/HOS细胞中实现c-MET特异性降解(DC₅₀ = 199.9 nmol·L^-1), 且不影响同源蛋白MST1R。该体系通过特异性空间构型形成稳定的复合结构, 在骨肉瘤细胞中实现多靶点协同降解^[105]。实验证实, 这种双适配体系统能够选择性降解致癌信号通路关键蛋白, 而对同源蛋白家族成员无显著影响。在耐药性肿瘤模型中, 其降解效率显著优于传统小分子抑制剂, 并有效逆转耐药表型。

总体而言, 适配体与PROTAC技术的融合创新, 不仅拓展了靶向降解技术的应用边界(涵盖膜蛋白、转录因子复合物、非酶功能蛋白等传统难靶向目标), 更通过适配体的动态构象调控特性, 发展出光控降解、突变蛋白选择性清除等智能调控系统。其模块化架构支持双特异性适配体设计、药物协同整合及多功能纳米载体构建, 为个体化治疗提供了可编程的分子工具^[31,96]。

1.3　RNA靶向蛋白降解嵌合体

与靶向转录因子或利用适配体识别蛋白表位不同, RNA-PROTACs策略的创新之处在于直接利用RNA分子本身(如microRNA模拟物或特定序列RNA) 作为靶向模块。该策略特别适用于靶向RNA结合蛋白(RNA-binding proteins, RBPs)。RBPs长期因其独特的生物学特性而面临靶向治疗困境, 其通过特异性识别RNA结构元件, 在转录后调控、RNA代谢及选择性剪接等关键通路中发挥核心作用, 其功能异常与恶性肿瘤、神经退行性疾病等重大疾病密切相关^[106-108]。传统小分子药物开发模式在应对RBP靶向治疗时面临双重挑战, 平坦的RNA结合界面难以形成有效结合口袋, 同源家族成员的结构保守性导致选择性调控困难^[108]。靶向蛋白降解技术的革新为突破这一困境提供了全新视角, 其中RNA-PROTAC技术(表1) 通过整合RNA生物学与蛋白降解机制, 开创了基于核酸模拟物的精准治疗范式^[28]。

利用抑癌let-7家族的miRNA-PROTAC技术调控Lin28/let-7信号通路, 是该领域取得的重要突破进展。作为典型致癌RBP, Lin28通过结合let-7前体RNA抑制其成熟, 进而促进肿瘤干细胞特性维持^[109-111]。早期研究通过结构生物学手段解析了Lin28锌指结构域与RNA元件的相互作用模式, 发现其特异性识别GGAG序列的分子机制^[111]。基于此, 研究者采用硫代磷酸酯(PS) 和2′-O-甲氧乙基(2′-O-methyl, MOE) 修饰的短链RNA (AGGAGAU), 通过6-氨基己酸连接子共价偶联HIF-1α来源的VHL招募肽(LA[Hyp]YI), 在细胞模型中展现出显著的靶蛋白降解能力, 在2 μmol·L^-1浓度下可使Lin28A水平降低约50%^[112]。值得注意的是, 相较于传统RNA序列, 嵌合体表现出增强的结合亲和力, 揭示出E3连接酶招募产生的协同结合效应, 这为突破传统配体设计的活性瓶颈提供了重要启示。

利用pre-let-7与Lin28A的高亲和力特性, 作者通过系统优化连接臂和E3连接酶配体构建出miRNA-PROTAC, 实现对Lin28A的高效降解(图3)^[54]。在核酸序列优化方面, 作者系统筛选并验证了靶向Lin28A不同结构域[包括N端冷休克结构域(cold-shock domain, CSD)、C端锌指结构域(zinc finger domain, ZKD] 及全长pre-let-7f-1) 的寡核苷酸序列, 发现全长序列及CSD特异性序列展现出对Lin28A蛋白优异的结合力与降解效率; 在连接子设计上, 深入探索了碳链和聚乙二醇等多种类型及长度的连接子对降解活性的影响, 确定了特定长度的PEG连接子(P4) 与CRBN配体组合时效果最佳; 在E3连接酶选择方面, 对比了靶向CRBN和VHL的配体, 最终优选CRBN配体以最大化降解效率。基于此优化设计的let-7家族miRNA-PROTAC嵌合分子通过泛素-蛋白酶体途径实现靶蛋白Lin28的高效降解, 在仅100 nmol·L^-1的浓度下即可降解超过80%的Lin28A蛋白, 并显著上调了肿瘤抑制性let-7家族的miRNA表达水平。进一步机制研究表明, 这种双重调控作用不仅影响经典癌基因信号通路, 还能激活免疫相关因子和免疫调控网络, 实现多维的协同抗肿瘤效应。在荷瘤动物模型中, miRNA-PROTAC嵌合核酸与传统化疗药物联用展现出显著的协同治疗肿瘤效果, 可以显著抑制肿瘤生长并诱导肿瘤消退, 且未观察到明显系统毒性, 为临床转化奠定了重要基础。

RNA-PROTAC技术的成功标志着靶向降解领域正经历从“小分子中心主义”向多模态协同的范式转变。其创新价值不仅在于拓展了可成药靶点库, 更重要的是构建了从基础RNA生物学到临床治疗的转化桥梁。特别是在选择性剪接异常相关疾病(如脊髓性肌萎缩症、家族性乳腺癌) 中, 该技术可通过同时降解多个剪接调控因子, 如SRSF1^[113]、HNRNPA1^[114]等, 实现信号通路网络水平的病理调控, 为脊髓性肌萎缩症等遗传性疾病提供了新的治疗思路。随着冷冻电镜技术在RNA-蛋白复合物结构解析中的应用, 以及人工智能驱动的RNA三维折叠预测算法(如AlphaFold-RNA) 的突破, 未来有望实现“理性设计-智能优化-精准递送”的全链条创新, 有望推动1500余种RBP靶向治疗的临床转化^[33,34]。

RNA-PROTACs利用特定的RNA序列靶向RBPs。其特异性主要依赖于RNA序列与靶蛋白RNA结合域(RNA-binding domain, RBD) 的特异性识别。然而, 挑战在于: 许多RBPs属于多结构域蛋白或参与形成大型复合物(如剪接体), 其RBD可能具有广泛的RNA结合偏好性或识别短而保守的基序。这增加了使用单一RNA序列作为“弹头”时, 意外招募结合相似序列或结构元件的非靶标RBPs的风险(脱靶降解)。精确设计RNA序列长度、二级结构(如特定环区或凸起) 及结合位点的空间排布, 对于最大限度地提高其对目标RBP的特异性至关重要^[115]。

1.4　G四链体靶向蛋白降解嵌合体(G4-PROTACs)

G四链体(G-quadruplex, G4) 作为一类独特的核酸二级结构, 由富含鸟嘌呤的序列通过Hoogsteen氢键形成四链平面, 其稳定性依赖于中心阳离子的配位作用。这类G4结构广泛分布于基因组调控区域及mRNA的非翻译区, 通过动态构象变化参与转录调控、RNA剪接和翻译抑制等关键生物学过程^[116]。近年研究表明, G4结构与特定RNA/DNA结合蛋白的相互作用构成复杂调控网络, 在神经发育、肿瘤免疫及遗传性疾病中发挥重要作用^[117]。然而, 传统药物开发模式难以靶向这类缺乏明确配体结合域的蛋白, 促使研究者将蛋白降解靶向嵌合体技术与G4生物学特性相结合, 开创了基于G四链体结构的新型靶向降解范式(表1)。

基于G4的PROTAC技术核心在于利用G4序列作为“弹头”, 通过化学连接子将其与E3泛素连接酶配体偶联, 形成异双功能分子。当G4-PROTAC同时结合靶蛋白和E3连接酶时, 可诱导靶蛋白的泛素化修饰, 进而通过泛素-蛋白酶体系统实现特异性降解。Phan团队^[118]率先利用平行链G4 DNA (TTGGGT GGGTGGGTGGGT) 作为分子弹头, 并使用CRBN和VHL配体作为E3连接酶招募单元, 构建了可降解解旋酶RHAU/DHX36的双模式降解工具。通过合理设计G4核心序列并偶联不同E3连接酶配体, 成功实现了对靶蛋白的构象依赖性降解。研究表明, 偶联CRBN配体的G4-P的降解效率显著优于偶联VHL配体的分子。在HeLa细胞中, 仅需50 nmol·L^-1浓度处理24 h即可实现近完全的RHAU蛋白降解。

G4-PROTAC技术的核心优势在于其动态响应特性。Peng团队^[119]筛选出高亲和力G4 RNA序列, 将其与E3连接酶配体偶联构建了靶向脆性X智力低下蛋白(fragile X mental retardation protein, FMRP) 的降解分子(图4)。该研究设计的sc1-VHLL分子通过36 nt G-四链体RNA (sc1∶5′-GCUGCGGUGUGGAAGG AGUGGCUGGGUUGCGCAGCG-3′) 靶向FMRP蛋白的RGG结构域, 利用GSGS肽链(Gly-Ser-Gly-Ser) 连接VHL E3连接酶配体ALAPYIP (Ala-Leu-Ala-Pro-Tyr-Ile-Pro), 在肿瘤微环境高K⁺浓度下通过泛素-蛋白酶体途径有效清除靶蛋白FMRP的降解, 在CT26细胞中, 400 nmol·L^-1 sc1-VHLL处理24 h显著降解约75%的FMRP蛋白, 在HeLa细胞中, 600 nmol·L^-1 sc1-VHLL处理24 h同著降解70%的FMRP蛋白。FMRP的降解重塑了肿瘤免疫微环境, 发挥上调促炎因子表达和减少免疫抑制因子分泌的协同效应。在荷瘤动物模型中, 负载该分子的纳米递送系统展现出优异靶向性, 显著增强免疫检查点抑制剂的治疗效果, 为逆转免疫治疗耐药提供了新思路。Chen团队^[120]创新性地利用bTERC衍生的RNA G-四链体序列(5′-GGGUUGCGG AGGGUGGGCCU-3′) 靶向DHX36蛋白, 通过PEG2链(-O-CH₂CH₂-O-CH₂CH₂-) 连接VHL配体AHPC, 实现了对解旋酶DHX36的特异性降解。相较于传统DNA-G4系统, RNA特有的结构特征显著增强了与靶蛋白的相互作用, 降解效率提高60%。在HeLa细胞中, 62.5 nmol·L^-1 rG4-PROTAC处理24 h可实现大于90%的DHX36降解。rG4-PROTAC诱导的DHX36降解不仅直接影响其介导的G4解旋功能, 同时还可通过稳定mRNA高级结构抑制下游基因翻译。在肌肉再生模型中, 该嵌合分子通过调控关键信号通路影响干细胞增殖能力, 为再生障碍性疾病干预开辟了新方向。这一发现突破了PROTAC技术的传统框架, 证明核酸结构不仅能介导蛋白降解, 还可通过调控RNA动态折叠影响基因表达网络。

天然的核酸G四链体结构与PROTAC技术的融合不仅突破了传统“不可成药”靶点的降解难题, 更通过结构生物学与化学生物学的交叉创新, 开辟了靶向蛋白降解的新维度。从构象特异性识别到微环境响应降解, 从单一蛋白清除到基因表达网络调控, 这一技术体系不断突破传统药物开发的边界。其模块化设计、动态可编程特性及多模式作用机制, 为肿瘤免疫治疗、神经退行性疾病和遗传性疾病的精准干预提供了全新策略。随着纳米递送技术、化学修饰策略和计算设计工具的进步, G4-PROTAC有望在精准医学时代实现从“概念验证”到“临床落地”的跨越, 最终推动肿瘤、免疫和遗传疾病治疗范式的根本性变革。

1.5　其他新型的核酸PROTACs

除了上述几种核酸PROTAC以外, 核酸-PROTAC的设计理念还在不断拓展。研究者们利用核酸的其他特性开发了更多创新性的靶向降解工具, 进一步丰富了该技术体系的应用范围。Wei课题组相继开发出端粒靶向嵌合体(TeloTACs)^[121]和甲基化CpG结合蛋白靶向降解嵌合体(methyl-CpG-PROTAC)^[122]两大技术平台(图5, 表1)。TeloTACs通过模拟端粒重复序列(TTAGGG) 特异性结合端粒保护蛋白TRF1/2, 设计并筛选了18种长烷基链/PEG连接臂, 并偶联VHL配体形成双功能分子, 利用泛素-蛋白酶体系统靶向降解shelterin复合物核心组分。实验证实在5 μg·mL^-1质量浓度处理24 h后, 上述降解剂在HeLa细胞中可降解高达90%以上的TRF2蛋白, 进而导致端粒长度缩短和肿瘤细胞增殖抑制, 为靶向端粒稳态调控网络提供了新工具。针对表观遗传调控关键因子甲基化CpG结合蛋白2 (MeCP2), 该团队创新性地采用含甲基化胞嘧啶的DNA寡核苷酸(5′-GTATCmCGGATACTTTGTATCC GGATAC-3′) 靶向MeCP2, 通过筛选不同的连接子(18种长烷基链/PEG连接臂) 与VHL配体偶联, 构建甲基化CpG-PROTAC分子。该策略通过模拟MeCP2天然底物——甲基化CpG位点, 实现对其特异性招募及降解, 在5 μg·mL^-1质量浓度处理24 h后, 上述降解剂在A375细胞中可降解高达70%以上MeCP2蛋白。上述两类核酸PROTAC技术均采用点击化学实现核酸与E3连接酶配体的精准偶联, 其模块化设计显著提升了蛋白降解剂构建的便捷性。同时, TeloTACs和methyl-CpG-PROTAC拓展了核酸PROTAC在端粒生物学及表观遗传调控领域的应用, 并有望提供靶向核酸-蛋白互作界面的药物研发的普适性策略。

2　技术挑战与创新性解决方案

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尽管核酸-PROTAC技术展现出巨大潜力, 其临床转化仍面临多重技术壁垒。其核心难点主要集中于分子稳定性、递送效率和靶向特异性3个关键挑战。

在核酸分子稳定性方面, 天然寡核苷酸易受血清核酸酶降解, 且肾脏清除速率快, 显著限制了其在生物体系中的应用, 通常需通过化学修饰提升其生物稳定性。例如, RNA-PROTAC研究显示, 通过引入2′-O-甲氧基糖环修饰可显著增强RNA稳定性, 有效提升其降解效率。miRNA-PROTAC则通过骨架硫代磷酸酯修饰, 实现血清稳定性提升^[123]。这种结构优化策略使得核酸-PROTAC在循环系统中的稳定性获得数量级提升, 为体内应用奠定基础, 但不同的核酸PROTACs对修饰的敏感性也不尽相同, 需要进一步筛选和优化。

此外, 核酸的递送效率一直是核酸药物研发的关键科学问题, 也是核酸PROTACs药物临床应用的核心挑战之一。由于核酸分子固有的负电性和大分子质量特性导致的细胞膜穿透障碍, 而传统转染试剂(如polyetherimide, PEI) 的细胞毒性限制了应用。因此, 合理设计靶向递送系统是突破细胞摄取屏障的关键。例如, CpG-STAT3D PROTAC利用TLR9配体的固有内吞特性实现免疫细胞靶向^[124], miRNA-PROTAC采用DNCA/CLD/PEG混合脂材包封提升细胞摄取^[125]等。随着众多新型核酸递送技术的涌现, 如具有器官特异性靶向功能的纳米递送系统等, 这类核酸PROTAC分子的递送效率和特异性将会得到显著提升^[74,126-133]。

核酸PROTACs特异性会因为靶点本身的多功能性或者其当前尚不为人知的功能而存在脱靶效应。基于人工智能(artificial intelligence, AI) 的计算生物学与结构设计策略正成为突破精准降解瓶颈的核心驱动力。以p53-R175H突变体为例, 研究者通过分子对接模拟解析突变体蛋白表面的构象特征, 设计出能够特异性识别致癌突变体的适配体结构, 实现突变体与野生型蛋白的精准区分, 为选择性降解提供分子基础^[35,96]。同时, 利用TNA-DNA复合物的双价结合策略也能显著增强对靶蛋白复合物的结合亲和力和特异性^[129,134]。随着AI预测工具的深度整合, 研究者能够更高效地预测靶蛋白-E3连接酶的协同结合界面, 指导模块化核酸序列的理性设计^[135,136]。这些创新策略的系统性整合, 正逐步突破核酸-PROTAC从实验室到临床的关键技术瓶颈。

3　总结与展望

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基于核酸的PROTAC技术通过整合核酸分子的序列特异性识别能力与靶向降解机制, 突破了传统小分子PROTAC在靶点选择性和分子设计上的双重限制, 为攻克“不可成药”靶点提供了革命性工具。从靶向转录因子的TRAFTACs、识别RNA结合蛋白的RNA-PROTAC, 到利用核酸适配体aptamer-PROTACs和G四链体结构的G4-PROTACs, 这些创新核酸PROTAC构建策略通过核酸分子的精准识别、动态构象调控及模块化设计, 实现了对转录因子复合物、RNA结合蛋白、表观遗传调控因子等传统难靶向目标的高效降解。随着化学修饰、递送系统及人工智能技术的进步和在核酸药物中应用, 核酸PROTAC药物的研发领域有望在精准医学中实现突破, 为癌症、罕见病等多种不同适应症的治疗开辟全新的范式。

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2025年第60卷第11期

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doi: 10.16438/j.0513-4870.2025-0456

接收时间：2025-04-22
首发时间：2026-09-20
出版时间：2025-11-12

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收稿日期：2025-04-22
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北京大学药学院, 天然药物及仿生药物全国重点实验室和化学生物学中心, 北京 100191

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汤新景, Tel: 86-10-82805635, E-mail: xinjingt@bjmu.edu.cn

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 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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Type	Target	Application scenario	Nucleic acid element	Synthesis technology	Key feature
TF-PROTAC	NF-κB/P65	Liver cancer	NF-κB binding sequence; DNA duplex	BCN-azide click chemistry	Blocks IL6/STAT3 inflammatory signaling
	Brachyury	Notochord development regulation	Brachyury binding sequence	Covalent conjugation with Cas9 CRISPR guide RNA	CRISPR-dCas9 targeted; embryonic validation
	STAT3	Diffuse large B-cell lymphoma	STAT3 binding sequence; DNA duplex	DBCO-azide click chemistry	Immune-cell delivery; overcomes tumor barriers
	LEF1	Prostate cancer	LEF1 binding sequence; DNA duplex	Phosphoramidite monomer; solid-phase synthesis	Inhibits β-catenin/LEF1 signaling
	ERG	Prostate cancer	ERG binding sequence; DNA duplex	Phosphoramidite monomer; solid-phase synthesis	Blocks EMT
	c-Myc/Max	Triple-negative breast cancer	TNA aptamer-E-box chimera	TNA-DNA bivalent linkage	Degrades c-Myc/Max heterodimer
	Nrf2-MafG	Non-small cell lung cancer	Nrf2-MafG binding sequence; DNA duplex	Alkyne-azide click chemistry	Degrades Nrf2-MafG heterodimer
Aptamer-PROTACs	BET	Breast cancer	AS1411 aptamer	Amide bond formation	Enhances tumor targeting
	Nucleolin	Breast cancer	AS1411 aptamer	DBCO-azide click chemistry	Tumor-selective uptake; reduced toxicity
		Breast cancer	AS1411 aptamer	Alkyne-azide click chemistry	Tumor-specific; photo-activatable
	BRD4	Liver cancer; melanoma	High-affinity aptamer (bead-selected)	Bead display-FACS functional screening platform	Function-driven screening
	p53-R175H mutant	Lung cancer	Mutant conformation-specific RNA aptamer	Alkyne-azide click chemistry	Mutant-specific targeting
	ERα	Hormone-dependent breast cancer	ER dimerization interface aptamer	Solid-phase synthesis with photocleavable linker	Spares DNA-binding domain
	c-MET	Osteosarcoma	c-MET specific aptamer	Complementary pairing of dual aptamers	Degrades oncogenic pathways; reverses resistance
RNA-PROTAC	Lin28A	Cancer cells	Lin28A ZKD-targeting sequence	Maleimide-SH conjugation	First RBP degrader
	RBFOX1	Neurons; breast cancer cells	RBFOX1 RNA recognition motif	Maleimide-SH conjugation	Selective splicing factor degradation
	Lin28A	Breast cancer	pre-let-7 miRNA mimic	Amide bond formation	Dual action: degrades Lin28A & restores let-7 maturation
G4-PROTAC	RHAU/DHX36	Cancer cells	DHX36-targeting DNA G-quadruplex	Alkyne-azide click chemistry	Validates G4-PROTAC concept
	DHX36	Gene regulation; muscle regeneration	DHX36-targeting RNA G-quadruplex	Alkyne-azide click chemistry	Inhibits muscle stem cell proliferation
	FMRP	Tumor immunotherapy	FMRP-targeting RNA G-quadruplex	DBCO-azide click chemistry	Reprograms tumor microenvironment
TeloTAC	TRF1/2	Telomere-related cancers	Telomeric repeat sequence (TTAGGG)	BCN-azide click chemistry	Induces telomere shortening
Methyl-PROTAC	MeCP2	Epigenetic regulation	Methylated DNA	BCN-azide click chemistry	Selectively kills MeCP2-overexpressing cancer cells

Type

Target

Application scenario

Nucleic acid element

Synthesis technology

Key feature

TF-PROTAC

NF-κB/P65

Liver cancer

NF-κB binding sequence; DNA duplex

BCN-azide click chemistry

Blocks IL6/STAT3 inflammatory signaling

Brachyury

Notochord development regulation

Brachyury binding sequence

Covalent conjugation with Cas9 CRISPR guide RNA

CRISPR-dCas9 targeted; embryonic validation

STAT3

Diffuse large B-cell lymphoma

STAT3 binding sequence; DNA duplex

DBCO-azide click chemistry

Immune-cell delivery; overcomes tumor barriers

LEF1

Prostate cancer

LEF1 binding sequence; DNA duplex

Phosphoramidite monomer; solid-phase synthesis

Inhibits β-catenin/LEF1 signaling

ERG

Prostate cancer

ERG binding sequence; DNA duplex

Phosphoramidite monomer; solid-phase synthesis

Blocks EMT

c-Myc/Max

Triple-negative breast cancer

TNA aptamer-E-box chimera

TNA-DNA bivalent linkage

Degrades c-Myc/Max heterodimer

Nrf2-MafG

Non-small cell lung cancer

Nrf2-MafG binding sequence; DNA duplex

Alkyne-azide click chemistry

Degrades Nrf2-MafG heterodimer

Aptamer-PROTACs

BET

Breast cancer

AS1411 aptamer

Amide bond formation

Enhances tumor targeting

Nucleolin

Breast cancer

AS1411 aptamer

DBCO-azide click chemistry

Tumor-selective uptake; reduced toxicity

Breast cancer

AS1411 aptamer

Alkyne-azide click chemistry

Tumor-specific; photo-activatable

BRD4

Liver cancer; melanoma

High-affinity aptamer (bead-selected)

Bead display-FACS functional screening platform

Function-driven screening

p53-R175H mutant

Lung cancer

Mutant conformation-specific RNA aptamer

Alkyne-azide click chemistry

Mutant-specific targeting

ERα

Hormone-dependent breast cancer

ER dimerization interface aptamer

Solid-phase synthesis with photocleavable linker

Spares DNA-binding domain

c-MET

Osteosarcoma

c-MET specific aptamer

Complementary pairing of dual aptamers

Degrades oncogenic pathways; reverses resistance

RNA-PROTAC

Lin28A

Cancer cells

Lin28A ZKD-targeting sequence

Maleimide-SH conjugation

First RBP degrader

RBFOX1

Neurons; breast cancer cells

RBFOX1 RNA recognition motif

Maleimide-SH conjugation

Selective splicing factor degradation

Lin28A

Breast cancer

pre-let-7 miRNA mimic

Amide bond formation

Dual action: degrades Lin28A & restores let-7 maturation

G4-PROTAC

RHAU/DHX36

Cancer cells

DHX36-targeting DNA G-quadruplex

Alkyne-azide click chemistry

Validates G4-PROTAC concept

DHX36

Gene regulation; muscle regeneration

DHX36-targeting RNA G-quadruplex

Alkyne-azide click chemistry

Inhibits muscle stem cell proliferation

FMRP

Tumor immunotherapy

FMRP-targeting RNA G-quadruplex

DBCO-azide click chemistry

Reprograms tumor microenvironment

TeloTAC

TRF1/2

Telomere-related cancers

Telomeric repeat sequence (TTAGGG)

BCN-azide click chemistry

Induces telomere shortening

Methyl-PROTAC

MeCP2

Epigenetic regulation

Methylated DNA

BCN-azide click chemistry

Selectively kills MeCP2-overexpressing cancer cells