天然药物靶向DNA G-四链体的研究

王凯波 ,  王莹莹 ,  Jonathan Dickerhoff ,  杨丹洲

工程（英文） ›› 2024, Vol. 38 ›› Issue (7) : 48 -61.

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工程（英文） ›› 2024, Vol. 38 ›› Issue (7) : 48 -61. DOI: 10.1016/j.eng.2024.03.015
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天然药物靶向DNA G-四链体的研究

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DNA G-Quadruplexes as Targets for Natural Product Drug Discovery

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摘要

DNA G-四链体（G4s）是由富含鸟嘌呤（G）的DNA序列中两个或多个G-四链体堆叠形成的特殊DNA二级结构。这些结构在高度转录的基因（特别是在与癌症相关的癌基因）中发挥关键作用，使其成为癌症治疗的重要靶点。值得注意的是，靶向癌基因启动子区的G4结构为解决“不可成药”或耐药蛋白质（如MYC、BCL2、KRAS和EGFR）的靶向难题提供了新策略。天然产物一直以来是药物发现的重要来源，特别是在癌症和传染病领域。近年来，天然来源的DNA G4靶向药物研究取得了显著进展。包括MYC-G4、BCL2-G4、KRAS-G4、PDGFR-β-G4、VEGF-G4和端粒-G4等多种G4结构已被证实是小檗碱、端粒抑素、喹叨啉碱、血根碱、isaindigotone等天然产物的潜在作用靶点。本文系统总结并评价了天然及天然衍生DNA G4稳定剂的最新研究进展，重点关注天然来源小分子对DNA G4s结构的识别机制；同时探讨了DNA G4s靶向药物开发所面临的挑战和机遇。

Abstract

DNA guanine (G)-quadruplexes (G4s) are unique secondary structures formed by two or more stacked G-tetrads in G-rich DNA sequences. These structures have been found to play a crucial role in highly transcribed genes, especially in cancer-related oncogenes, making them attractive targets for cancer therapeutics. Significantly, targeting oncogene promoter G4 structures has emerged as a promising strategy to address the challenge of undruggable and drug-resistant proteins, such as MYC, BCL2, KRAS, and EGFR. Natural products have long been an important source of drug discovery, particularly in the fields of cancer and infectious diseases. Noteworthy progress has recently been made in the discovery of naturally occurring DNA G4-targeting drugs. Numerous DNA G4s, such as MYC-G4, BCL2-G4, KRAS-G4, PDGFR-β-G4, VEGF-G4, and telomeric-G4, have been identified as potential targets of natural products, including berberine, telomestatin, quindoline, sanguinarine, isaindigotone, and many others. Herein, we summarize and evaluate recent advancements in natural and nature-derived DNA G4 binders, focusing on understanding the structural recognition of DNA G4s by small molecules derived from nature. We also discuss the challenges and opportunities associated with developing drugs that target DNA G4s.

关键词

G-四链体 / 天然产物 / 生物碱 / 癌症 / 启动子

Key words

G-quadruplex / Natural products / Alkaloids / Cancer / Promoter

引用本文

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王凯波,王莹莹,Jonathan Dickerhoff,杨丹洲. 天然药物靶向DNA G-四链体的研究[J]. 工程（英文）, 2024, 38(7): 48-61 DOI:10.1016/j.eng.2024.03.015

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1 引言

DNA四链体（G4s）作为新型抗癌药物靶点的概念起源于20世纪80年代末[1‒2]，但其结构基础可追溯到1962年首次观察到的鸟嘌呤（G）衍生物自组装成四链结构[3]。端粒G4（在接近生理条件下由真核生物染色体的端粒单链富含G的DNA序列形成），是首个被证实的生物体内G4实例[1,4‒5]。1997年，端粒G4结合小分子被发现可抑制端粒酶的活性[6]。2002年研究人员在人癌基因MYC启动子区发现了G4（MYC-G4），为DNA G4在癌基因表达中的生物学意义提供了初步证据，并阐明通过与G4相互作用的小分子稳定G4，可以下调癌基因表达[7]。这项研究引起了学界对非端粒G4s的关注，确立了以MYC-G4为模型系统，靶向癌基因启动子G4s作为癌症治疗的替代策略。此后，包括KRAS-G4、PDGFR-β-G4、BCL-2-G4、c-KIT-G4、VEGF-G4和EGFR-G4等大量癌基因启动子G4s相继被发现[8‒15]。2009年Elizabeth Blackburn、Carol Greider和Jack Szostak获得诺贝尔生理学或医学奖，以表彰他们对端粒和端粒酶的发现。此后，G4s作为极具潜力的抗癌药物靶标受到了广泛关注。除了与癌症的关联外，G4s还与神经退行性疾病[16‒17]、病毒及寄生虫感染[18‒19]等多种疾病密切相关。例如，GGGGCC重复序列的异常扩增与额颞叶痴呆（FTD）和肌萎缩侧索硬化症（ALS）发病相关[17]。解旋酶缺陷可能导致G4s在转录组和基因组中异常积累，引发范科尼贫血（FANCJ缺陷）、原始侏儒症（BLM缺陷）、Werner综合征（WRN缺陷）等严重先天性疾病[17,20]。散发性阿尔茨海默病、严重家族性凝血障碍、特应性皮炎、心肌梗死、耳聋等疾病的发病机制也被发现与G4结构动态失衡存在关联[21]。G4s在DNA二级结构中的独特多样性为开发针对个体G4s的特异性药物提供了机会。

DNA G4s是由两个或多个G-四分体堆叠而成的核酸二级结构，这些G-四分体由富含G序列中的四个鸟嘌呤以环形排列并通过Hoogsteen氢键连接形成。G-四分体的稳定堆叠还需要单价阳离子（如K+或Na+）参与与鸟嘌呤上的O6原子之间的配位作用[22‒23]，如图1（a）所示[22‒23]。尽管G4s可以在分子间或分子内形成，但大多数生物学上相关的G4s是指分子内形成的，由包含三个四分体的核心组成[24]。有趣的是，不同于结构相对均匀的双链，G4s具有较高的结构多样性[24]，如图1（b）所示，因为它们在G束的方向性、环类型、环长度或环序列方面可以变化。此外，G4s在覆盖外部四分体的帽子结构上也表现出多样性。例如，MYC-G4和VEGF-G4是符合G4形成规律的典型右手平行型G4s，具有G≥3(N1-7G≥3)≥3的共识序列[24]，如图1（c）所示。端粒hybrid-1和hybrid-2 G4s是由三个平行取向的G-束和一条反平行取向的G束组成的混合结构，以不同的顺序排列，如图1（c）所示[24]。相比之下，KRAS-G4、PDGFR-β-G4和EGFR-G4分别代表鼓包型G4、缺口G4和折返l型G4拓扑结构，它们不同于典型的G4结构[15,24]，如图1（c）所示。此外，hTERT-G4是一个独特的三级DNA G4结构，由两个G4单元通过端对端堆叠形成，中间通过长达26个碱基的环状连接区桥接[图1（c）]，是目前已知的首例该类型三维构象的报道实例[25]。这些不同的G4结构能够与各种蛋白质相互作用以执行特定的生物学功能[26]。G4s在DNA二级结构中的独特多样性为开发针对个别G4s的特定药物提供了可能。

通过G4特异性抗体和化学探针技术，研究者已在人类基因组中定位了DNA G4s，并在活细胞中实现可视化观测[27‒31]。在G4诱导条件下，人类基因组理论上可形成超过70 000个G4s位点[32]。然而，迄今仅在染色质和活细胞中鉴定出大约10 000个G4结构[30‒31]。这些发现表明，DNA G4形成是一个动态过程，其丰度与特定的染色体结构、基因组特征及细胞状态密切相关。此外，G4形成序列在关键基因调控区域（如5'-非翻译区域、癌基因启动子和端粒）高度富集[30‒31]。作为表观遗传调控因子，DNA G4通过调控基因转录、翻译和复制、维持基因组稳定性和端粒功能，深度参与多种细胞生物学进程[26‒27,33]。DNA G4s的存在与癌症和神经退行性疾病相关的高度转录的基因密切相关[27,34]。在人类癌细胞中，DNA G4结构的形成具有细胞周期依赖性，始终处于折叠与解旋的动态平衡状态。G4稳定剂可通过推动平衡向折叠态偏移，阻断G4与转录因子或功能蛋白的相互作用，从而抑制癌基因表达并诱导肿瘤细胞死亡[31]。此外，G4结构的异质性分布与乳腺癌分子分型显著相关，为个体化治疗策略开发提供新思路[35]。基于这些特性，DNA G4s已被确立为癌症治疗新靶标，特别是在靶向传统“不可成药”或耐药性蛋白（如MYC、EGFR、KRAS和PDGFR-β）等领域具有独特优势[36‒37]。

天然产物及其衍生物一直在药物发现中发挥着重要作用，特别是在治疗癌症和传染病的药物中[38‒39]。目前获批的抗癌药物中超过60%源于天然产物，包括紫杉醇、替尼泊苷、喜树碱和长春新碱等经典药物[39]。天然产物在结构复杂性和功能多样性方面具有固有优势[38]，在靶向G4药物开发中独具价值。研究表明，端粒抑素、喹叨啉i、小檗碱、黄连素、表小檗碱及血根碱等天然产物及其衍生物，可以高亲和力结合DNA G4lai 发挥抗癌活性（图2）[37,40‒44]，而这些化合物只是天然产物中具有DNA G4结合活性的一小部分。

本文系统综述天然来源DNA G4稳定剂的最新研究进展，重点解析天然小分子与DNA G4结合复合物的结构特征，并讨论基于天然产物的DNA G4靶向药物开发面临的挑战与机遇。

2 端粒抑素及其衍生物是有效的端粒G-四链体稳定剂

人类端粒通常由5~8 kb富含鸟嘌呤的d(TTAGGG) n DNA重复序列组成，其3'端为携带150~200个核苷酸的单链染色体悬垂结构突出端[45‒47]。通常，每轮DNA复制会导致端粒缩短50~200个碱基，当端粒DNA缩短至临界长度时，细胞将进入衰老和凋亡阶段[46,48]。然而，在大多数肿瘤细胞中特异性激活的端粒酶，通过逆转录酶活性维持端粒长度，在细胞永生化进程中起关键作用[48‒49]。近生理溶液条件下，人类端粒富G序列可以形成两种G4构型，即hybrid-1和hybrid-2 [24]。小分子稳定剂通过锁定端粒G4s构象，可以有效抑制端粒酶或端粒替代延长（ALT）途径介导的端粒延伸，最终导致端粒DNA缩短与肿瘤细胞死亡[24,50‒51]。因此，开发端粒G4稳定剂已成为一种有效的抗癌策略，并得到了广泛的研究支持[24,52‒58]。

端粒抑素（telomestain）是从链霉菌Streptomyces annulus 3533-SV4中分离的天然大环化合物，由七个𫫇唑环和一个噻唑啉环组成（图2）[59]。该化合物通过稳定端粒G4s来特异性抑制端粒酶的活性，其半最大抑制浓度（IC50-TRAP）值为5 nmol·L-1，远比其他报道的G4相互作用分子更有效[42,59]。此外，端粒抑素对多种癌细胞展现出强抗肿瘤活性，同时对正常细胞的毒性极低，因此被认为是极具潜力的抗癌候选药物，吸引了大量的研究关注[57,60]。然而，其水溶性差与获取难度大等问题，限制了其进一步的临床转化研究[61‒62]。

值得注意的是，许多改善了物理学和生物学特性的端粒抑素衍生物已被报道[57,63‒69]。其中，含有六个𫫇唑环和两条烷基胺侧链的化合物——L2H2‒6M(2)OTD（L2H，见图2），显示出与端粒抑素相当的细胞活性（IC50-TRAP = 20 nmol·L-1）[57]。在生理条件下，烷基胺侧链带正电荷，可与带负电的端粒G4磷酸骨架发生静电相互作用，并提高水溶性。Chung等[60]解析了端粒hybrid-1 G4与L2H结合复合物的核磁共振（NMR）溶液结构（图3），发现L2H破坏端粒hybrid-1 G4的5'末端帽子结构中原有的T-A碱基对，转而通过堆叠在5'末端外部G-四分体上，形成广泛的π-π堆叠相互作用。两个烷基胺侧链与核苷酸磷酸基团的静电相互作用，是维持强结合亲和力的关键。该结构是目前唯一解析的人类端粒G4与端粒抑素衍生物结合的复合物结构，为设计端粒G4靶向药物提供了重要的结构基础。基于此，研究者合成了许多含功能基团修饰的L2H衍生物[63,66‒68,70]。

3 喹叨啉及其衍生物作为MYC G-四链体稳定剂

除端粒DNA G4s外，癌基因启动子G4s也引起了极大关注，尤其是MYC癌基因启动子G4 [22]。稳定癌基因启动子G4结构以调节下游基因表达已成为新型癌症治疗策略[8,22]。Hurley课题组的开创性研究发现：MYC近端启动子区域形成的DNA G4（MYC-G4），可作为基因转录抑制元件，其稳定性可被G4靶向的小分子调控从而抑制MYC转录。这项工作为后续KRAS、PDGFR-β、BCL-2、c-KIT、VEGF等癌基因启动子G4研究建立了范式[8‒14]。

MYC作为关键“驱动”癌基因，在超过80%的人类癌症中异常高表达[71‒73]。MYC癌蛋白在肿瘤细胞增殖、分化、转移和耐药性中发挥关键作用，是重要的癌症治疗靶标[71‒73]。但是，由于其蛋白结构表面平坦，缺乏药物结合口袋，而被长期视为“不可成药”靶点[72‒74]。值得关注的是，小分子与MYC-G4的结合和稳定可以有效抑制MYC基因表达，最终导致癌细胞死亡[7]。这使得，MYC-G4成为间接调控MYC信号通路的替代靶标，受到癌症研究领域的广泛关注。

本实验室在2005年首次解析了自由态MYC-G4的主要结构[75]。然而，寻找具有高亲和力和特异性的小分子配体用于复合物结构解析始终面临挑战[24]。经过六年的持续探索，我们最终通过核磁共振技术解析了MYC-G4与喹叨啉i（一种喹叨啉衍生物）复合物高分辨率NMR溶液结构，这是首个被小分子识别的生物学相关启动子G4复合物结构[76]，如图3（b）所示。喹叨啉i是天然吲哚并喹啉类生物碱白叶藤碱的衍生物[77]。白叶藤碱从非洲三角叶白叶藤（Cryptolepis triangularis N.E.Br.）中分离得到，具有抗菌、抗炎和抗癌活性等多种生物活性[77‒78]。值得注意的是，白叶藤碱在中非和西非国家已被用作抗疟药物[41,78]。2000年研究发现白叶藤碱及其衍生物具有抗肿瘤活性，这可能与其和DNA G4的相互作用有关[79]。基于此，研究者合成了许多白叶藤碱衍生物，其中喹叨啉i等化合物显示出显著的MYC-G4稳定能力 [41,80‒81]。

喹叨啉i对MYC-G4的NMR滴定数据显示出高质量波谱特征，满足复合物结构解析要求[76]。据此确定的2∶1喹叨啉i-MYC-G4结合复合物结构揭示了多个创新性结合特征：喹叨啉i诱导的侧翼残基重排形成特异性结合口袋，见图3（b）[76]。喹叨啉i通过招募相邻的侧翼残基A6或T23形成“准三联平面”，以末端堆叠方式锚定在MYC-G4的外侧G-四分体上。喹叨啉i的结合过程涉及静电和π-π堆积相互作用，即二乙基氨基官能团与DNA磷酸骨架发生静电相互作用，而芳香环系统则通过π-π堆积稳定化合物。这是首个揭示DNA G4能同时被两个小分子同时结合的三维结构研究。值得注意的是，新月形的喹叨啉i仅覆盖G-四分体的两个鸟嘌呤进行π堆积，这与端粒抑素、TMPyP4等对称环状分子显著不同（后者通过与外部G-四分体的所有四个鸟嘌呤均匀重叠以实现最大的堆积相互作用）。

然而，对称性环状分子往往表现出较低的G4选择性，而像喹叨啉、奎氟沙星这样的不对称骨架小分子更容易实现特异性结合。这一发现为开发高选择性G4靶向药物提供了新思路：基于新月形分子骨架进行理性设计，可有效提升靶标识别精度。事实上，受喹叨啉i启发，后续研究已从天然产物与合成化合物库中筛选出多个具有G4特异性结合的小分子[36,82‒90]。

4 小檗碱及其衍生物作为端粒和启动子G-四链体稳定剂

当前，G4靶向化合物的选择性仍面临重大挑战——多数分子难以有效区分不同DNA G4亚型。典型案例如小檗碱（Berberine），这是一种广泛存在于黄连等药用植物中的天然异喹啉生物碱[91‒92]。小檗碱具有广泛的药理作用，涉及其与蛋白质和核酸的相互作用，如抗癌、抗炎、抗菌和降糖活性，并已在中药方剂中使用了数百年[91‒92]。最新研究发现，小檗碱及其衍生物可作为有效的G4稳定剂，揭示了该分子骨架在药物开发中的新功能机制[37,93]。但值得关注的是，小檗碱对DNA G4结构缺乏选择性，可以结合端粒G4和许多癌基因启动子G4s。

4.1 小檗碱以6∶2的化学计量比结合人端粒平行G4

2013年，研究人员通过X射线衍射确定了首个与小檗碱结合的DNA G4复合物结构，当时发现六个小檗碱与人端粒序列形成平行G4二聚体结合[94]。在确定的晶体结构中，两对小檗碱分子通过凹面互配形成共平面，堆叠在平行端粒G4的外侧G-四分体上（图4）。有趣的是，来自两个不同DNA单体的A2和T13残基通过Watson-Crick氢键相连，在5'末端位点形成结合口袋，容纳配对的小檗碱[94]。这种药物稳定的5'-5'端G4二聚体呈现6∶2（小檗碱:G4 ）结合模式[94]。但需指出，该晶体结构的生物学意义有限，因其可能与晶体堆积有关而不是溶液中真实的6∶2复合物形式。尽管如此，从该晶体结构中得到的二聚体结合模式仍被广泛用于指导开发靶向G4的小檗碱衍生物[95‒97]。

4.2 小檗碱和黄连碱靶向MYC和KRAS启动子G4

通过1H NMR滴定实验，我们发现小檗碱更倾向于与平行型DNA G4（MYC和KRAS启动子G4）结合。与晶体复合结构显示的二聚体结合模式不同，溶液状态下小檗碱以单体形式与MYC-G4结合[解离常数（K d）≈ 9.9 μmol·L-1]，结合化学计量比为2∶1 [97]。质谱数据明确显示了两个主要高亲和力结合位点，这与之前报道的晶体固态中的6∶2结合模式不同[94,97]。2∶1小檗碱-MYC-G4复合物的NMR溶液结构表明，小檗碱招募侧翼残基形成配体-碱基共平面，分别堆叠在5'或3'外侧G-四分体上，且每个结合位点可以观察到两种分子取向[图5（a）和（b）]。有趣的是，两种构象通过约180°旋转对称相关[图5（a）和（b）]，平行型G4s外侧G-四分体和侧翼残基形成的宽结合口袋使结合配体更加灵活，具有不同的构象。

KRAS-G4作为转录调节因子，是小分子靶向抑制KRAS表达的重要靶标[9]。KRAS是人类基因组中突变率较高的基因之一，与多种人类癌症的发生发展相关[37,98]。尽管KRAS-G4在十多年前已经被发现，并且已报道了许多KRAS-G4结合化合物，但迄今为止还未解析出高分辨率的KRAS-G4-配体结合复合物结构，这严重阻碍了KRAS-G4靶向药物的进一步开发[37]。2022年，我们解析了KRAS-G4与天然产物小檗碱（K d ≈ 0.55 μmol·L-1）和黄连碱（K d ≈ 0.50 μmol·L-1）结合复合物的NMR溶液结构[37]。复合物结构中再次观察到2∶1的结合化学计量比和碱基招募机制，提示这是小檗碱衍生物在溶液状态下与平行型G4结合的关键共性特征（图6）。KRAS-G4包含一个独特的胸腺嘧啶鼓包，该鼓包在自由态下通过Watson-Crick氢键与侧翼残基腺嘌呤配对。然而，随着小檗碱和黄连碱的结合，原始的A-T碱基对被破坏，形成腺嘌呤-配体共平面，堆叠在3'端G-四分体上。鼓包胸腺嘧啶部分覆盖了结合的配体，并参与3'端结合口袋的形成（图6）。这个独特的胸腺嘧啶鼓包可以作为一个结合基团，增强配体对KRAS-G4的选择性。此外，黄连碱的亚甲二氧五元环与腺嘌呤H61形成额外氢键，增强复合物的稳定性。尽管如此，4-核苷酸（nt）环残基没有参与结合口袋的形成，这可能值得进一步探索。基于确定的结合复合物结构，可以通过在C1、C12和C13位置引入侧链设计高选择性KRAS-G4靶向的小檗碱衍生物。

4.3 小檗碱靶向PDGFR-β基因启动子中形成的dGMP填充型缺口G4

缺口G4（vG4）是一种独特的DNA G4，由三个G3链和一个G2链构成，因此在不完整的G-四分体中有一个G-空缺[99‒100]。由于G-空缺的存在，vG4s比常规的G4s稳定性差[99]。但G-空缺可以被环鸟苷酸单磷酸（cGMP）或脱氧鸟苷-5'-单磷酸（dGMP）等鸟嘌呤衍生物特异性填充，为通过设计利用G-空缺作为锚点的小分子鸟嘌呤偶联物，开发选择性vG4靶向药物提供了新策略[101‒102]。此外，填充vG4s的形成表明与细胞内鸟嘌呤代谢物浓度相关的潜在基因调控机制，并暗示了新药开发的新机会[101,103‒105]。2020年，我们解析了PDGFR-β启动子首个dGMP填充型vG4的 NMR溶液结构[101]，并发现天然产物小檗碱可以特异性结合并稳定该结构（K d ≈ 1.6 μmol·L-1）[93]。小檗碱-dGMP-vG4三元复合物在钾溶液中的NMR结构显示（图7）：每个小檗碱招募两个侧翼序列中的腺嘌呤残基形成“准三联平面”，堆叠在填充缺口vG4的外侧G-四分体上，结合过程涉及π-π堆叠和静电相互作用。与MYC-G4复合物类似，两个结合位点均存在次要配体构象（图5和7）[93,97]。这是首个解析的小分子-填充型vG4复合物结构，为设计G4靶向小檗碱衍生物提供了结构参考。

4.4 表小檗碱特异性结合人端粒hybrid-2 型 G4

表小檗碱是小檗碱衍生物，其甲氧基和亚甲二氧基的位置不同（图2）[106]。本实验室在2007年首次解析了人端粒hybrid-2 型 G4（Tel2G4）的生物相关结构[51]，但历经近十年才找到能特异性结合该结构的配体[106]。2018年，我们使用NMR解析了Tel2G4与表小檗碱（K d ≈ 0.016 μmol·L-1）复合物的溶液结构（图8）[53,106]。与2∶1结合化学计量比结合启动子G4的小檗碱不同，表小檗碱特异性地结合到Tel2G4的5'端G-四分体，诱导侧翼残基和5'端位点处的TTA环重排形成一个适配良好的结合口袋。表小檗碱通过招募侧翼腺嘌呤形成氢键配体-碱基共平面，堆叠在5'端外侧G-四分体顶部，同时被T:T:A三联层和T:T碱基对通过π-π堆叠相互作用覆盖，构建出迄今最复杂的四层结合口袋。

值得注意的是，结构相似的小檗碱（K d ≈ 1.99 μmol·L-1）、黄连碱（K d ≈ 0.33 μmol·L-1）和巴马汀（K d ≈ 0.74 μmol·L-1）不能很好地结合到Tel2G4 [53]，表明甲氧基和甲醚二氧基的取代位点是特异性识别的关键。尤为重要的是，表小檗碱对Tel2G4点的高特异性可以在生理条件下驱动其他端粒G4结构转化为hybrid-2型，这是首次报道的此类实例。这项研究提供了配体与人类端粒G4相互作用结构的见解，并为端粒G4靶向药物设计提供了结构范式。

5 其他天然产物DNA G4稳定剂

鉴于人类DNA G4s的结构多样性和多态性，从天然产物中寻找高选择性稳定剂具有显著优势。实际上，除了上述讨论的G4结合天然生物碱之外，已报道的天然DNA G4稳定剂还包括：司他霉素 A [107]、血红素[108]、秋水仙碱[109]、佩加哈尔明 D [84]、血根碱[40]、白屈菜红碱[40]、胡椒碱[110]、木兰花碱[111]、雷公藤甲素[112]、药根碱[113]、防己诺林碱[114]、吴茱萸碱[114]、异靛酮[58]、喹唑啉[115]和丝裂真菌素衍生物[116]。

司他霉素A（一种典型的DNA小沟稳定剂）以4∶1的结合比例与分子间平行[d(TGGGGT)]4 G4的两个相对沟槽结合，其结合常数（K b）值为(4.0 ± 3.0) × 106 L·mol-1 [107]。这一发现提示，可以通过将G4配体与DNA双链稳定剂结合，设计新型G4结合化合物，从而提高G4的特异性和亲和力。此外，灵活的DNA双链稳定剂可以将两个G4结合化合物连接在一起，形成一个夹子状配体用于稳定锚定，该方法受到人工G4探针（G4P）蛋白的启发[31]。血红素（一种刚性的天然大环化合物）通过金属螯合刚性大环结合C9orf72基因G4（K d ≈ 3 µmol·L-1）。这种相互作用增强了过氧化物酶活性，与ALS和FTD等神经退行性疾病的发展有关[117]。正离子中心和芳香大环骨架是G4结合化合物的天然特征，引起了研究者在结构修饰方面的极大关注。一般来说，阳离子中心和侧链是主要的修饰对象，由五价锰(III)-卟啉复合物[缔合常数（K a）= 108 L·mol-1]-人类端粒G4和具有显著G4结合特异性的卟啉桥联四核铂复合物[118‒123]代表。在发现的G4结合天然产物中，许多化合物具有新月形骨架，并展现出显著的G4稳定活性，如血根碱（K a ≈ 1.16×106 L·mol-1-KRAS-G4）[124]、药根碱（K a ≈ 0.90×106 L·mol-1-KRAS-G4）[124]和白屈菜红碱（K d ≈ 0.25 μmol·L-1-VEGFA-G4）[125]。对正常细胞的毒性限制了药根碱和白屈菜红碱的药物潜力[126‒127]。然而，结构修饰可能有助于减少这些副作用。值得注意的是，丝裂真菌素不是一种具有相对灵活碳骨架的刚性新月形化合物，但其分子内氢键极大地促进了化合物的平面性，从而提高了其G4结合亲和力[116,128]。因此，在确保一定程度的灵活性的同时，考虑引入形成氢键的片段以增强其他可能化合物的平面性是可行的。三级氮中心也可以季铵化以引入正电荷，从而增强与富含电子的G4s的相互作用[129‒130]。许多研究都对新月形天然产物进行了结构修饰，以提高对G4的结合特异性和药理活性[131‒133]。鉴于许多G4-配体结合复合物的结构尚未确定，理解这些产物对G4s的分子识别并利用这些知识设计新型天然衍生药物至关重要。

6 基于天然产物设计DNA G4靶向药物的挑战与机遇

天然小分子-G4复合物结构研究为靶向人启动子G4与端粒G4提供了重要理论依据。像端粒抑素衍生物这样的大环分子，在大小上与G-四分体相似，可以直接覆盖端粒hybrid-1 G4外部G-四分体的全部四个鸟嘌呤，实现强效π-π堆叠和静电相互作用。这些大环分子通常对不同拓扑结构的DNA G4具有高亲和力和低选择性，这使得它们难以特异性结合特定的G4。相比之下，带有合适官能团的新月形小药效团（如小檗碱、表小檗碱和喹叨啉）更有可能以特定的方式结合到生物学相关的分子内G4s。由于新月形小分子只覆盖两个鸟嘌呤，它们通常会招募一个侧翼残基形成“准三联体平面”，该平面堆叠在外部G-四分体上，实现特异性结合G4。与强调骨架长度和灵活性以适应双链DNA的螺旋拓扑结构的DNA小沟稳定剂[134‒137]不同，新月形G4结合化合物的特点是扩展的芳香环系统、带正电荷的中心和可修饰的侧链。新月形药效团中心带正电荷的氮原子通常位于G-四分体带负电的羰基上方，从而产生强静电相互作用。此外，配体和招募的侧翼残基之间可能存在的氢键相互作用是增强特异性相互作用的重要因素，如喹叨啉i与MYC-G4、表小檗碱与端粒G4、黄连碱与KRAS-G4的结合。同时，可修饰的带正电荷的侧链将与G4s的沟槽或磷酸骨架发生空间和静电相互作用，从而为特异性识别不同DNA G4s提供额外作用。总的来说，最佳小分子利用包括空间效应、π-π堆叠、氢键和静电相互作用在内的一系列相互作用，来特异性识别单个G4s，这些相互作用只能通过NMR溶液结构研究来识别。

当前G4靶向药物研发的主要挑战是G4选择性。由于多数G4具有保守的四分体核心与短环结构，传统配体难以区分相似拓扑结构的G4。值得注意的是，最近发现的独特G4s（如vG4 [101,104‒105]、鼓包型G4 [37]和含茎环型的G4 [138‒140]）可能为开发特定的G4靶向药物提供了机会，因为这些G4s具有与经典G4s不同的特征，可以用于更具选择性的配体设计。例如，受双重特异性靶向方法[141‒142]的启发，可以将天然G4结合配体与特定的DNA双链稳定剂偶联，以靶向特定的茎环G4s或具有合适沟槽的G4s。同样，天然配体可用鸟嘌呤类似物修饰，通过部分促进vG4s的完整性，实现vG4特异性结合[93,102,104,143]。对于具有鼓包或环的G4s，可以通过柔性碳链将天然化合物与互补的碱基类似物偶联，以实现可能的互补配对和氢键结合。除了具有特殊结构拓扑或序列组成的G4s，G4s相邻的解旋单链DNA可以成为配体-“寡核苷酸”复合物（如配体-肽核酸（PNA）偶联物）的靶点[144‒145]。据报道，可以与G4侧翼序列杂交的PNA和G4配体萘二酰亚胺（NDI）的偶联物，能特异性结合人类免疫缺陷病毒（HIV）-1长末端重复（LTR）区域内的G4，表明其在获得性免疫缺陷综合征（AIDS）治疗中的潜力[144]。值得注意的是，在设计配体-PNA偶联物时，应考虑细胞膜的通透性。还可以利用卤化铂修饰实现与侧翼或环碱基的共价结合，减少脱靶效应并用于癌症的有效治疗[146‒147]。此外，可以向配体添加碳水化合物以提高对癌细胞G4s的选择性[87,148‒149]。由于配体偶联物的研究很少涉及天然产物，应进一步实验以验证上述策略的可行性。另一方面，可以考虑天然和天然衍生化合物的对映选择性，以提高G4s靶向的特异性。许多合成金属络合物已经表现出对特定G4s的对映选择性[150‒155]；然而，人们对与G4结合活性相关的天然和天然衍生化合物的手性效应了解较少。对于具有手性碳的配体骨架，应进一步研究其手性效应。例如，据报道，衍生物（S）-端粒抑素比天然（R）-端粒抑素具有更高的端粒-G4结合和端粒酶抑制活性[52]。Pegaharmarine D是一对外消旋体，可以特异性结合平行型G4，并对癌细胞表现出显著的抑制活性，但其手性对G4结合和生物活性的影响尚无研究[84]。由于许多生物碱是手性的且具有不同的药理活性，通过特定的结构分析，阐明配体对映选择性与G4亲和力-选择性之间的关系将具有重要意义。总的来说，上述策略可以结合使用，以实现更特异的G4靶向以及更高的治疗效果。

G4靶向药物研发面临的另一个挑战是新发现的天然生物碱在全球范围内的及时流通和共享。从陆地和海洋生物（包括植物、真菌和细菌）中分离出成百上千种具有不同骨架的新型生物碱[156‒163]，它们中的许多具有芳香平面和带正电荷的中心。特别是，许多海洋生物碱具有天然卤素基团，已发现这些基团可以通过吸电子来稳定π-π堆叠[16,4‒166]。卤素基团还可以帮助提高配体的脂溶性和生物利用度[116]。Tajuddeen等[167]报道了一类新的从植物中分离出的具有新型轴向手性N,C-偶联萘骈异喹啉生物碱，可能具有结合G4s的潜力。然而，这些新发现的天然生物碱的G4结合活性筛选受到其来源、合成和商业化的限制。另一个原因可能是G4s是新发现的小分子靶标，并不像双链DNA和蛋白质等靶标那样广为人知。事实上，自2001年发现以来，端粒抑素是唯一已知的从微生物中分离出来的G4结合天然配体，并且已经被大量衍生化以提高生物活性[57,59]。因此，还有许多新型天然产物有待测试和衍生化，以评估它们的G4结合潜力，这将推动基于G4相互作用的天然或天然衍生药物发现领域的发展。

目前，一个较大的争论是是否有必要针对特定的G4进行疾病治疗。已发现癌症和其他疾病细胞比正常细胞有更多的G4s，以及更明显的基因组不稳定性。许多报道的G4结合化合物被发现可以结合不同的G4s，并对正常细胞几乎没有或没有毒性的情况下表现出显著的抗癌活性 [20,168‒170]。如前所述的小檗碱，被发现可以结合端粒和MYC、KRAS、PDGFR-β启动子中形成的G4s，并抑制非小细胞肺癌（NSCLC）细胞的增殖。因此，考虑追求多重G4靶向治疗复杂疾病是值得的。然而，对于由一个或几个典型异常基因（如EGFR和KRAS突变，以及C9orf72六核苷酸重复）引起的疾病或与合成致死性相关的疾病[8,27,117,171]，个体G4靶向将是一种有效的治疗方法，具有更高的安全性，因此仍然是药物设计的重要方向。“癌基因成瘾”假说认为，某些癌症依赖于一个或几个驱动基因来生长和存活，并确定了适当的癌症靶标[172‒173]。因此，通过作用于启动子G4s来靶向异常表达的基因可能是癌症治疗中新型药物开发的有效途径，特别是作为“不可成药”和耐药蛋白（如MYC、KRAS和EGFR）的替代策略。总的来说，需要更多的细胞和动物水平上进行更多的实验验证，以阐明个体G4靶向和多重G4靶向策略的优缺点。

7 结论

天然产物因其构成了一个庞大且结构多样的化合物库，而在药物设计中具有显著的重要性和独特优势，为新药研发提供了丰富的参考资源和衍生化基础。大量研究表明，G4s作为表观遗传和调控元件，参与了复制、转录和翻译等过程中的各种异常生物学过程。G4s的形成能够抑制DNA甲基化并影响核小体组装，这使得G4s成为特殊的表观遗传标记。此外，G4s的形成可能导致位点突变、基因缺失-连接、转座、重排和拷贝数变化，这些是基因组不稳定性及疾病发生的重要原因[174‒175]。启动子区域的G4s可以诱导转录因子的结合，甚至可能通过促进长程相互作用（包括启动子-增强子相互作用和染色质环化）来改变染色质结构并调控基因表达，这些相互作用由染色质重塑蛋白和长环G4形成介导[176‒180]。R-环的形成和稳定也与G4s的形成密切相关[176,181]。由G4s介导的长距离相互作用和R-环，连同调控蛋白，可能促进液-液相分离（LLPS）以确保有效的生物学过程[26]，这在癌细胞的快速增殖和营养掠夺中非常突出。然而，具体机制仍需实验确认。此外，编码区域中G4s的异常形成会导致复制叉停滞、转录和翻译终止，就像一个简单的“路障”，从而影响细胞稳态并引起病理损伤。为了维持有序的生命活动，通常需要解旋酶和其他核酸结合蛋白在正常细胞中解开G4s，这也涉及DNA损伤修复途径[174,182‒184]。一旦G4s形成-解开的平衡被破坏，并且由于先天或环境因素导致DNA修复错误，就可能发生癌症等疾病。因此，除了蛋白质靶向外，利用不同于双链DNA（dsDNA）的四链体结构特征开发G4靶向药物是明智的。靶向G4s的天然药物可以与G4结合蛋白竞争并阻碍基因表达，起到“刹车”作用，从而为疾病治疗提供了一种有前景的策略。

G4-配体复合物的结构分析可以提供有关配体结合机制和新药设计的信息。基于已确定的复合物结构，明显可以看出天然小分子通过包括π-π堆叠、氢键、静电相互作用和立体效应在内的一系列相互作用，特异性识别G4s。最好通过NMR溶液结构分析来研究这些配体-G4复合物在近生理条件下的特定结合模式，因为结晶通常由于晶体堆积产生人工配体-G4复合物，如在晶体条件下观察到的6∶2小檗碱-G4晶体结构。与直接覆盖整个G4平面进行π-π堆叠和静电相互作用的大环分子不同，新月形小药效团可以招募侧翼残基形成“准三联体平面”，该平面堆叠在外部G-四分体上，促进广泛的π-π堆叠和静电相互作用。在“准三联体平面”中观察到特定的氢键相互作用，这促成了更高的结合亲和力。基于天然产物的特定结构修饰对于提高这些化合物对G4s的选择性和生物活性非常必要。

开发各种小分子修饰策略以增强G4结合特异性和亲和力，使得靶向单个G4s更加可行，而靶向多个G4s则成为治疗复杂疾病的重要策略。Pidnarulex（CX-5461）作为一种首创的G4靶向化合物，目前正在进行临床评估，用于治疗BRCA1/2缺陷的乳腺癌和卵巢癌患者[169]。由于G4形成与肿瘤进展显著相关，G4结合药物的开发将为疾病治疗打开新的窗口。应测试更多的新型天然生物碱（尤其是来自海洋生物和内生真菌的生物碱）的G4结合能力和药理活性；同时，配体-G4复合物结构分析对于指导性药物衍生化至关重要。由于天然产物历来是先导药物的重要来源，我们相信未来会发现更多天然存在的G4靶向药物，并具有卓越的G4选择性和高效的疾病治疗效果。

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