编者按：从阿司匹林的“意外诞生”，到如今不断攻克“不可成药”靶点，共价药物走过了一条跨越百年的进化之路。截至2025年，已有超过50款共价药物获批上市，在肿瘤、感染以及神经系统疾病等领域展现出独特价值。如何更高效、精准地发现这类药物，仍是摆在行业面前的一道关键难题。依托一体化、端到端的CRDMO赋能平台，药明康德致力为全球合作伙伴提供覆盖共价药物发现与开发的一体化解决方案。本文将重点介绍药明康德在共价药物发现领域的能力布局与实践。
共价药物的百年进化
1899年，一种名为乙酰水杨酸的化合物以阿司匹林之名正式上市，用于缓解疼痛与炎症。这一现代药物史上的里程碑事件，也在无意间揭开了共价药物的序幕。
传统小分子药物与靶蛋白之间，通常依赖非共价相互作用。这种结合更像一次短暂的“握手”，药物一旦被代谢清除，疗效便随之消失。
而共价药物，则提供了另一种可能。
它们通过亲电基团，与靶蛋白的特定氨基酸形成共价键。这个过程就如同用钥匙插入目标蛋白的“锁孔”，以“先结合、再锁定”的方式延长药效持续时间。
尽管阿司匹林早已惠及无数患者，但其作用机制却在数十年后才揭晓。20世纪70年代，科学家发现阿司匹林通过乙酰基亲电基团与环氧化酶的丝氨酸残基结合，形成共价键。这一发现不仅解释了其药理机制，也让“共价抑制”的概念逐渐清晰。
类似的故事并不罕见。青霉素、头孢菌素、磷霉素等经典抗生素，都是在临床成功多年之后，人们才真正理解其共价作用机制。
由于对共价药物可能引发脱靶效应的担忧，这类分子在药物研发中曾长期被边缘化。随着这些“意外发现”的分子不断在临床上证明其价值，局面开始改变。
进入21世纪，通过药物理性设计，BTK抑制剂伊布替尼（ibrutinib）与EGFR抑制剂阿法替尼（afatinib）等共价抑制剂相继问世。近年来，共价药物的研发进入新阶段。通过系统性筛选与特定残基共价结合的配体，共价药物叩开了曾经“不可成药”靶点的大门，促成了sotorasib、adagrasib等KRAS G12C抑制剂的诞生。
如今，已有超过50款共价药物获FDA批准上市。共价机制所带来的高效力、长作用时间以及对新靶点空间的拓展，使其成为当下药物研发的重要方向之一。
共价药物的快速发展也对筛选技术提出了更高要求。从共价化合物库高通量筛选，到片段筛选以及DNA编码化合物库（DEL）等新兴技术，这些方法正不断开拓共价药物发现的新路径，也为这一跨越百年的药物故事开启新的篇章。
共价DEL打开共价筛选新空间
在共价药物的发现过程中，药明康德生物学业务平台团队就曾面临着一项挑战。他们需要为具有促癌效应的糖酵解酶PGAM1设计共价抑制剂，但棘手之处在于，这一靶点的活性口袋中，并没有共价药物最常用的反应位点半胱氨酸。
在共价药物发现中，半胱氨酸通常是首选“攻击目标”。其携带的巯基反应活性强，易于与亲电基团形成稳定的共价键。但这一策略也有明显的局限性。在人体的蛋白质组中，半胱氨酸仅占约2%。这意味着，大量潜在靶点缺乏可利用的反应位点。PGAM1正是其中的典型。
破局的关键，来自于药明康德持续建设的DEL技术平台。
在DEL体系中，每个化合物都连接着一段独特的DNA标签。当数百万甚至数十亿个携带标签的化合物与靶蛋白共同孵育，研究人员只需读取标签，便能快速锁定高亲合力的苗头化合物，大幅提升了筛选效率。
早在2018年，当DEL仍属于一项少数实验室掌握的复杂技术时，为了让这项技术成为每一位科研人员都能轻松使用的药物发现工具，药明康德生物学业务平台启动了DEL平台建设。从零起步，仅用数月首个DEL产品初步成型；一年后，平台迎来了首位客户。
如今，随着DELopen、DELight、DELpro等产品的陆续推出，DEL平台已成为药明康德新药发现体系的基石之一，每年为客户执行数百次筛选，覆盖数十亿级别的化合物空间。
在共价药物发现领域，药明康德生物学业务平台多年前也已建立起共价DEL（cDEL）能力。2023年，随着共价化合物库的升级，cDEL平台持续扩展，形成覆盖可逆与不可逆共价药物发现的完整体系。
例如，针对不可逆共价药物发现，DELink Pro平台涵盖了16亿化合物和184种专门设计的共价亲电基团，并提供可定制的一站式解决方案；而在可逆共价领域，平台也构建了超过4亿化合物、涵盖39类亲电基团的筛选能力。
值得一提的是，这一平台不再局限于半胱氨酸位点，而是将筛选范围拓展至赖氨酸、丝氨酸、酪氨酸等多种氨基酸残基。此外，新型亲电基团的引入，也让筛选具有更高的特异性与更低的脱靶风险。
在PGAM1项目中，基于这一综合性能力，药明康德团队利用不可逆和可逆共价DEL技术，鉴定并验证了一类靶向酪氨酸的新型抑制剂。得益于cDEL库中多样化的亲电基团，这类抑制剂引入了未曾使用过的非经典亲电基团结构。
正如这一案例所展示的，依托cDEL平台，共价药物的“可探索空间”正被系统性地打开。
新进展：系统评估共价DEL亲电基团
cDEL平台能力的提升，不仅依赖于规模扩展，还需要方法的完善。在一项发表于Helvetica Chimica Acta的近期研究中，药明康德生物学业务平台团队与苏黎世联邦理工学院合作，对共价DEL亲电基团的适用性进行了系统性评估。
这项研究聚焦于cDEL面临的反应性与稳定性问题：高反应性的亲电基团可能会导致选择性下降，此外不同亲电基团的稳定性差异显著。若缺乏系统评估，可能直接影响筛选结果的可靠性。
为此，研究团队选取了59种具有代表性的亲电基团，覆盖8大类结构类型。其中，6类用于形成不可逆共价键，包括芳基卤化物、烯烃、炔烃等；另外2类（醛和腈类）则倾向于形成可逆共价键。
▲该研究对59种亲电基团的DEL适用性进行了系统评估（图片来源：参考资料[1]）
在模拟真实DEL构建流程的条件下，研究团队首先对各类亲电基团的偶联效率进行了系统评估。在59种候选亲电基团中，有45种能够以超过50%的效率成功偶联，具备良好的DEL兼容性。
在此基础上，研究团队进一步考察了这45种亲电基团对半胱氨酸和赖氨酸这两类氨基酸残基的反应活性、选择性，以及候选亲电基团的反应速度、稳定性等指标。
最终，研究团队筛选出21种具有高偶联效率以及反应活性的亲电基团，这些亲电基团在后续检验中均表现出了良好的稳定性。值得一提的是，醛和腈类可逆亲电基团在此次实验中均未能稳定存在，表明后续研究中，需要额外的化学步骤将其转化为稳定形式。
这项研究系统评估了化学性质各异的亲电基团在共价DEL中的适用性，有望为未来共价DEL的理性设计提供参考。
构建一体化共价药物发现引擎
cDEL并不是孤立存在的技术。在药明康德生物学业务平台的共价药物发现平台中，cDEL与共价片段药物发现（cFBDD）、共价高通量筛选（cHTS）技术深度融合，共同构成了协同互补的综合性发现引擎。
其中，cHTS平台以大规模共价化合物库为基础，构建了高效的苗头化合物发现引擎。cHTS共价库包含约6.9万个分子，涵盖50多种不同类型的共价亲电基团，能够作用于9类氨基酸残基，将筛选范围从传统单一位点拓展至更广泛的蛋白质空间。cHTS平台还提供了“direct to biology”（D2B）解决方案，为苗头化合物的发现，以及从苗头到先导提供全方位支持。
药明康德的cFBDD平台则从“更小”的分子片段出发，提供另一条高效的共价药物发现路径。该平台基于一个包含2600余个结构多样化片段的化合物库，并通过引入带有亲电基团的片段，快速识别可作为优化起点的共价结合物。这一策略尤其适用于结构复杂、“不可成药”的靶点。
一百多年间，共价药物完成了一场从偶然发现到理性设计的跨越。而这场跨越的背后，是筛选技术的一次次突破与迭代。
如今，药明康德cDEL、cHTS、cFBDD等技术平台协同，为客户提供系统性的解决方案，也让共价药物发现进入更加系统化的新阶段。
依托端到端、一体化CRDMO赋能平台，药明康德致力于加速突破性疗法的开发，帮助合作伙伴将创新成果高效转化为造福全球患者的解决方案，以践行“让天下没有难做的药，难治的病”的愿景。
了解WuXi Biology如何赋能药物研发，请长按扫描上方二维码，与药明康德生物学业务平台联系
From Aspirin to Targeting KRAS: These Technologies Are Redrawing the Frontiers of Drug Discovery
From the “accidental birth” of aspirin to recent advances against previously “undruggable” targets, covalent drugs have evolved for over a century. As of 2025, over 50 covalent drugs have been approved, demonstrating unique value in oncology, infectious diseases, neurological disorders and beyond. It has remained a central challenge to discover covalent molecules more efficiently and precisely. Leveraging its integrated, end-to-end CRDMO platform, WuXi AppTec is committed to providing global partners with integrated solutions for covalent drug discovery and development. This article highlights WuXi AppTec’s capabilities and practices in covalent drug discovery.
A Century-Long Evolution of Covalent Drugs
In 1899, a compound known as acetylsalicylic acid was officially launched under the name aspirin to relieve pain and inflammation. This milestone in modern pharmaceutical history also inadvertently marked the beginning of covalent drugs.
Traditional small-molecule drugs rely on non-covalent interactions with target proteins. Such binding resembles a transient “handshake”, once the drug is metabolized and cleared, its therapeutic effect dissipates.
Covalent drugs, however, offer a different paradigm.
They contain electrophiles that form covalent bonds with specific amino acid residues on target proteins. This process can be likened to inserting a key into a lock, enabling a “docking & locking” mechanism that prolongs the duration of action.
While aspirin has benefited countless patients, its mechanism of action was not elucidated until decades later. In the 1970s, scientists discovered that aspirin forms a covalent bond with a serine residue in cyclooxygenase via its acetyl electrophile. This finding not only explained its pharmacological activity but also helped define the concept of covalent inhibition.
Such stories are far from rare. Classic antibiotics such as penicillins, cephalosporins and fosfomycin achieved clinical success long before their covalent mechanisms were fully understood.
Due to concerns about potential off-target effects, covalent drugs were once sidelined in drug development. However, as these “accidentally discovered” molecules continued to prove their clinical value, perceptions began to shift.
Entering the 21st century, rational drug design enabled the emergence of covalent inhibitors such as the BTK inhibitor ibrutinib and the EGFR inhibitor afatinib. In recent years, covalent drug discovery has entered a new phase. Through systematic screening of ligands that form covalent bonds with specific residues, researchers have unlocked previously “undruggable” targets, leading to the development of KRAS G12C inhibitors such as sotorasib and adagrasib.
To date, more than 50 covalent drugs have been approved by the FDA. Their high potency, prolonged duration of action, and ability to expand the target landscape have made covalent mechanisms a key direction in modern drug discovery.
The rapid progress of covalent drugs has also raised the bar for screening technologies. From high-throughput screening of covalent libraries to fragment-based approaches and DNA-encoded libraries (DEL), emerging technologies are continuously opening new avenues for covalent drug discovery, ushering in a new chapter in this century-long journey.
Covalent DEL Expands the Landscape of Covalent Screening
In the course of covalent drug discovery, WuXi Biology (a business unit of WuXi AppTec) once encountered a notable challenge: designing covalent inhibitors for the pro-oncogenic glycolytic enzyme PGAM1. The difficulty lay in the absence of cysteine within the enzyme’s active site.
Cysteine is the most commonly targeted reactive residue for covalent drugs due to the high reactivity of its thiol group, which readily forms stable covalent bonds with electrophiles. However, this strategy has clear limitations. Cysteine accounts for only about 2% of residues in the human proteome, leaving many potential targets without accessible reactive sites. PGAM1 is a representative example.
The progress came from WuXi Biology’s continuously evolving DEL platform.
In a DEL system, each compound is tagged with a unique DNA tag. When millions—or even billions—of tagged compounds are incubated with a target protein, researchers can rapidly identify high-affinity hits by decoding the tags, dramatically improving screening efficiency.
As early as 2018, when DEL remained a technically demanding approach mastered by only a few laboratories, WuXi Biology initiated the construction of its DEL platform with the goal of making it broadly accessible for all researchers. Starting from scratch, the first DEL offering took shape within months, and the platform welcomed its first client after a year.
Today, with the launch of products such as DELopen, DELight and DELpro, the DEL platform has become a cornerstone of WuXi AppTec’s drug discovery engine, enabling hundreds of screening campaigns annually across chemical spaces encompassing billions of compounds.
In the field of covalent drug discovery, WuXi Biology established its covalent DEL (cDEL) capabilities years ago. In 2023, with the expansion of its covalent compound libraries, the cDEL platform further evolved into a comprehensive system, supporting both reversible and irreversible covalent drug discovery.
For example,in irreversible covalent discovery, the DELink Pro platform covers 1.6 billion compounds and 184 specifically designed covalent electrophiles, offering customizable, one-stop solutions.In the reversible covalent space, the platform supports screening of over 400 million compounds incorporating 39 classes of electrophiles.
Notably, the platform is no longer limited to cysteine-targeting strategies.It has expanded screening to multiple amino acid residues, including lysine, serine and tyrosine.The introduction of novel electrophiles also enhances specificity while reducing off-target risks.
In the PGAM1 project, leveraging this integrated capability, WuXi Biology utilized both irreversible and reversible cDEL technologies to identify and validate a novel type of tyrosine-targeting inhibitors. Thanks to the diversity of electrophiles in the cDEL library, these inhibitors incorporate previously unexplored, non-classical electrophile structures.
As this case illustrates, the “explorable space” for covalent drug discovery is being systematically expanded through cDEL.
New Advances: Systematic Evaluation of cDEL Electrophiles
Enhancing cDEL capabilities requires not only scale expansion but also methodological refinement. In a recent study published in Helvetica Chimica Acta, WuXi Biology’s team collaborated with ETH Zurich to systematically evaluate the applicability of covalent DEL electrophiles.
The study addressed key challenges in cDEL related to reactivity and stability. Highly reactive electrophiles may compromise selectivity, while stability can vary significantly across different electrophile types. Without systematic evaluation, these factors may constrain the reliability of screening outcomes.
To this end, the research team selected 59 representative electrophiles spanning eight structural classes. Six classes were designed to form irreversible covalent bonds, including aryl halides, alkenes, alkynes and beyond, while two classes—aldehydes and nitriles—tended to form reversible covalent bonds.
▲The study systematically evaluated the suitability of 59 electrophilic warheads for DEL applications.
Under conditions simulating real DEL construction workflows, the team first evaluated the coupling efficiency of each electrophile. Of the 59 candidates, 45 achieved a coupling yield above 50%, demonstrating ideal DEL compatibility.
Building on this, the team further assessed the reactivity and selectivity of these 45 electrophiles toward cysteine and lysine residues, as well as key parameters such as reaction kinetics and stability.
Ultimately, 21 electrophiles were identified that combined high coupling yield with strong reactivity, all of which also demonstrated high stability in subsequent evaluations. Notably, reversible electrophiles failed to maintain stability under the tested conditions, indicating that additional chemical steps may be required to improve their stability for future applications.
This study provides a systematic assessment of chemically diverse electrophiles within the cDEL framework and offers valuable guidance for the rational design of future covalent DEL libraries.
Building an Integrated Engine for Covalent Drug Discovery
cDEL does not operate in isolation. Within WuXi Biology’s covalent drug discovery platform, cDEL is deeply integrated with covalent fragment-based drug discovery (cFBDD) and covalent high-throughput screening (cHTS), forming a synergistic and complementary discovery engine.
The cHTS platform, built on large-scale covalent compound libraries, serves as an efficient hit identification engine. Its library comprises approximately 69,000 molecules featuring more than 50 distinct electrophile chemotypes.The library is purpose-built to target nine different amino acid residues, expanding screening beyond single-site approaches to broader protein space. The platform also offers “direct to biology” (D2B) solutions, providing end-to-end support from hit discovery to hit-to-lead optimization.
Meanwhile,WuXi AppTec’s cFBDD platform starts from smaller molecular fragments, offering another efficient pathway for covalent drug discovery.Based on a library of over 2,600 structurally diverse fragments, the platform incorporates electrophiles to rapidly identify covalent binders that serve as starting points for optimization. This strategy is particularly well-suited for structurally complex or traditionally “undruggable” targets.
Over more than a century, covalent drugs have evolved from serendipitous discoveries to rationally designed therapeutics, driven by continuous advances in screening technologies.
Nowadays, WuXi AppTec’s integrated platforms, including cDEL, cHTS, and cFBDD, work in concert to deliver systematic solutions for clients, ushering covalent drug discovery into a more systematic era.
Leveraging its end-to-end, integrated CRDMO platform, WuXi AppTec is committed to accelerating the development of breakthrough therapies, enabling partners translate innovation into solutions that benefit patients worldwide, and advancing its vision of “every drug can be made, and every disease can be treated.”
参考资料：
[1] Puff, Johanna, et al. "Systematic Evaluation of Electrophile Reactivity and Stability for Covalent DNA‐Encoded Libraries." Helvetica Chimica Acta (2026): e70064. https://doi.org/10.1002/hlca.70064
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