從幾十億分子中“讀”出答案，這項(xiàng)技術(shù)正重塑早期藥物發(fā)現(xiàn)流程

編者按：DNA編碼化合物庫（DEL）技術(shù)誕生30多年來，已從一項(xiàng)超越時代的前沿構(gòu)想，發(fā)展為重塑早期藥物發(fā)現(xiàn)流程的重要工具。憑借其高效的大規(guī)模篩選能力以及對“難以成藥”靶點(diǎn)的適用性，DEL顯著提升了潛力分子的發(fā)現(xiàn)效率，并已推動數(shù)款候選藥物進(jìn)入臨床開發(fā)階段。作為全球醫(yī)藥創(chuàng)新的賦能者，藥明康德?lián)碛谐墒焱晟频腄EL技術(shù)平臺，持續(xù)為全球合作伙伴提供針對多種分子類型的新藥發(fā)現(xiàn)服務(wù)，并依托一體化、端到端CRDMO平臺助力候選分子從科學(xué)前沿到臨床現(xiàn)實(shí)的轉(zhuǎn)化進(jìn)程。

1992年，時任Scripps研究所首任所長的Richard Lerner教授與諾獎得主Sydney Brenner教授共同發(fā)表了一篇超越時代的學(xué)術(shù)論文。經(jīng)過多年沉淀，論文中的構(gòu)想已經(jīng)成為深刻改變藥物發(fā)現(xiàn)流程的重要力量。

兩位科學(xué)家試圖解決的，是一個長期制約新藥發(fā)現(xiàn)效率的關(guān)鍵難題。

在新藥發(fā)現(xiàn)的最初階段，科學(xué)家常常面對這樣一幅畫面——一個巨大的“分子海洋”鋪陳眼前，數(shù)以億計的化合物靜靜沉睡其中。如何從這片汪洋里，撈到那根能精準(zhǔn)命中疾病靶點(diǎn)的“針”？

傳統(tǒng)篩選方法往往耗時漫長。但在新藥研發(fā)這場與疾病的賽跑中，時間從不等人。

正是在這樣的背景下，兩位科學(xué)家提出了影響深遠(yuǎn)的DNA編碼化合物庫（DNA-encoded library，DEL）技術(shù)。

在DEL技術(shù)中，每一個化合物都被“綁定”了一段獨(dú)一無二的DNA序列。這段序列就像化合物的身份標(biāo)簽，記錄著它的相關(guān)信息。

當(dāng)數(shù)十億個帶著特定標(biāo)簽的化合物與靶蛋白共同孵育，一場無聲的競賽隨之展開。誰能牢牢“抓住”靶點(diǎn)，誰就被保留下來。

而研究人員無需逐一分析這些化合物的結(jié)構(gòu)，只需檢測這些分子攜帶的標(biāo)簽，答案便一目了然。

那些高親合力的苗頭化合物就這樣快速浮出水面，走向后續(xù)的驗(yàn)證與分析。

隨著技術(shù)工具的發(fā)展，DEL技術(shù)在過去十多年間迅速崛起。如今，DEL已經(jīng)成為藥物發(fā)現(xiàn)領(lǐng)域的核心工具之一——一次性篩選數(shù)十億分子，讓新藥發(fā)現(xiàn)更高效、成本更低，為“難以成藥”的靶點(diǎn)和全新靶點(diǎn)的先導(dǎo)化合物發(fā)現(xiàn)打開新窗口。迄今為止，全球多款臨床候選藥物的發(fā)現(xiàn)，背后都有DEL的貢獻(xiàn)。

讓DEL技術(shù)觸手可及

幾年前，DEL還是少數(shù)實(shí)驗(yàn)室的“專屬技術(shù)”。對于許多初創(chuàng)生物技術(shù)公司和實(shí)驗(yàn)室而言，成本與技術(shù)門檻使得DEL依然是“只可遠(yuǎn)觀”的存在。

一個問題擺在面前——能不能把這項(xiàng)復(fù)雜的技術(shù)，變成人人都能使用的工具？

為了讓技術(shù)回歸初衷，2018年，藥明康德生物學(xué)業(yè)務(wù)平臺從零起步，開始建設(shè)DEL平臺。短短數(shù)月內(nèi)，首個DEL產(chǎn)品初步成型；一年后，平臺迎來了首位客戶，開始其賦能之旅。

經(jīng)過多年的發(fā)展，藥明康德生物學(xué)業(yè)務(wù)平臺陸續(xù)推出DELopen、DELight、DELpro等多種DEL產(chǎn)品，面向不同需求的學(xué)術(shù)界和產(chǎn)業(yè)界客戶開放。即使是一支僅有兩位科學(xué)家的初創(chuàng)團(tuán)隊(duì)，也能借助這些產(chǎn)品邁出創(chuàng)新藥發(fā)現(xiàn)的第一步。

“無論你是化學(xué)家還是生物學(xué)家，無論來自初創(chuàng)公司還是大型藥企，都能像使用常規(guī)實(shí)驗(yàn)工具一樣輕松上手。”藥明康德副總裁，生物學(xué)業(yè)務(wù)平臺首席科學(xué)官蒯樂天博士這樣描述建設(shè)DEL平臺的初衷。

真實(shí)故事往往比理念更具說服力。

一次合作中，一家大型藥企需要基于一個極具挑戰(zhàn)性的靶點(diǎn)篩選出能夠高效結(jié)合靶點(diǎn)的先導(dǎo)化合物。這項(xiàng)“看似不可能完成”的任務(wù)，被交到了藥明康德團(tuán)隊(duì)手中。

幾個月后，DEL篩選結(jié)果出來了。

藥明康德團(tuán)隊(duì)的篩選結(jié)果超出了最初的預(yù)期，找到了皮摩爾級親和力的分子——這意味著分子與靶點(diǎn)結(jié)合極為緊密，成藥潛力更高。

這項(xiàng)棘手任務(wù)的完成，成為新一輪合作的起點(diǎn)。此后，這家企業(yè)又與藥明康德展開了十余次合作，不斷推進(jìn)針對難開發(fā)靶點(diǎn)的新藥研發(fā)項(xiàng)目。

圖片來源：123RF

信任，就這樣一點(diǎn)點(diǎn)建立起來。

這個案例是藥明康德DEL平臺持續(xù)助力客戶加速新藥發(fā)現(xiàn)的真實(shí)寫照。如今，藥明康德生物學(xué)業(yè)務(wù)平臺每年執(zhí)行數(shù)百次DEL篩選，測試數(shù)十億級別化合物，廣泛覆蓋癌癥、神經(jīng)科學(xué)等多個領(lǐng)域。DEL這項(xiàng)技術(shù)，已經(jīng)成為新藥發(fā)現(xiàn)體系的基石之一。

拓展DEL的化學(xué)空間

提升篩選能力的同時，如何進(jìn)一步豐富DEL化合物庫中的分子類型與化學(xué)空間，成為新的挑戰(zhàn)。

在藥物研發(fā)中，分子的環(huán)狀骨架往往直接影響其生物活性。如果DEL化合物庫中缺少那些生物活性良好的關(guān)鍵骨架，再大規(guī)模的篩選，也可能與真正的候選分子擦肩而過。

因此，拓展DEL的化學(xué)空間，讓DEL化合物庫中的分子結(jié)構(gòu)類型更多樣、更接近真實(shí)藥物分子，也是藥明康德DEL平臺能力持續(xù)完善的重要方向。

在2025年的一項(xiàng)研究中，團(tuán)隊(duì)聚焦于兩個重要的環(huán)狀骨架——異惡唑啉（isoxazoline）和異惡唑（isoxazole）。

它們在多種小分子藥物中反復(fù)出現(xiàn)，表現(xiàn)出良好的生物活性。例如，從β-內(nèi)酰胺類抗生素中的抗菌、抗真菌成分，到某些鎮(zhèn)痛抗炎藥物，都能看到異惡唑的身影。

將這類關(guān)鍵骨架引入DEL化合物庫，對于提升篩選分子的成藥潛力具有重要意義。

然而，在DEL中構(gòu)建這類結(jié)構(gòu)絕非易事。

DEL的化學(xué)反應(yīng)必須在兼容DNA存在的條件下進(jìn)行，而后者對高溫、強(qiáng)酸強(qiáng)堿極其敏感，許多經(jīng)典有機(jī)合成方法根本無法直接使用。

既要構(gòu)建這些環(huán)狀骨架，又要高轉(zhuǎn)化率，同時還不能損傷DNA，幾乎是一場“刀尖上的舞蹈”。

在這項(xiàng)研究中，藥明康德生物學(xué)業(yè)務(wù)平臺以易得的醛類原料為起點(diǎn)，基于Huisgen環(huán)加成反應(yīng)進(jìn)行合成路線設(shè)計與優(yōu)化，最終在DNA連接狀態(tài)下實(shí)現(xiàn)了異惡唑和異惡唑啉環(huán)的高效構(gòu)建。

更重要的是，這一方法具有廣泛適用性。多種雜環(huán)醛、雙官能團(tuán)醛均可參與反應(yīng)，在不造成損傷的前提下生成目標(biāo)結(jié)構(gòu)。

化學(xué)空間，就這樣被進(jìn)一步拓展。而每一次化學(xué)空間的擴(kuò)展，都意味著篩選成功率的提升。

DEL技術(shù)的下一站

這個案例，只是藥明康德生物學(xué)業(yè)務(wù)平臺持續(xù)建設(shè)DEL平臺能力的一個縮影。

當(dāng)傳統(tǒng)小分子篩選日趨成熟，新分子浪潮帶來了新的挑戰(zhàn)。對于mRNA、多肽、分子膠、雙特異性蛋白降解分子等新分子類型，DEL面臨著更高的篩選難度。

以PROTAC?等雙特異性蛋白降解分子為例，它們需要同時識別兩個靶點(diǎn)——一個配體抓住目標(biāo)蛋白，另一個與E3泛素連接酶結(jié)合。

篩選難度，成倍增加。

為了應(yīng)對這類分子的挑戰(zhàn)，藥明康德生物學(xué)業(yè)務(wù)平臺團(tuán)隊(duì)構(gòu)建了一個包含超過40億個雙功能分子的專有DEL庫；此外，為提升篩選效率，開發(fā)了雙功能一珠一化合物（OBOC）DEL平臺。

不同于傳統(tǒng)液相DEL將分子混合篩選，OBOC-DEL把每個分子固定在獨(dú)立微珠上。

篩選時，這些微珠與目標(biāo)蛋白和E3連接酶共同孵育。只有與兩者共同構(gòu)成三元復(fù)合物的分子，才會被識別出來。

這個平臺在保留傳統(tǒng)DEL高通量篩選優(yōu)勢的同時，大大提升了對雙特異性蛋白降解候選分子的識別效率。

通過對OBOC-DEL技術(shù)的進(jìn)一步開發(fā)，團(tuán)隊(duì)正將傳統(tǒng)的“親和力篩選”拓展為“功能性篩選”——不僅評估分子與靶點(diǎn)的結(jié)合能力，還直接檢測其對蛋白活性與細(xì)胞功能的調(diào)控效果，從而篩選具備生物功能的候選分子。

DEL，還在持續(xù)進(jìn)化。

在技術(shù)持續(xù)迭代中，藥明康德DEL平臺正在幫助全球研發(fā)者縮短從科學(xué)假設(shè)到臨床候選分子的距離，加速將前沿科學(xué)轉(zhuǎn)化為造福患者的創(chuàng)新療法。

一枚分子被篩選出來，只是故事的開始。

在藥明康德一體化、端到端CRDMO平臺上，這些潛力分子可以繼續(xù)向下游推進(jìn)，完成化合物合成、結(jié)構(gòu)優(yōu)化與生物學(xué)驗(yàn)證等工作。一條完整的轉(zhuǎn)化路徑，已經(jīng)打通。

在這條路上，每一次化學(xué)反應(yīng)優(yōu)化、每一次篩選效率提升，最終指向的，都是同一個目標(biāo)——讓前沿科學(xué)成果，更快抵達(dá)患者。

From Molecular Ocean to Therapeutic Candidates: How DEL is Reshaping Drug Discovery

More than 30 years after its inception, DNA-encoded library (DEL) technology has evolved from a visionary concept into a transformative force in early-stage drug discovery. With its capacity for ultra-large-scale screening and its applicability to traditionally “undruggable” targets, DEL has dramatically enhanced the efficiency of hit identification and has already propelled several drug candidates into clinical development.

As an enabler of global pharmaceutical innovation, WuXi AppTec has established a comprehensive DEL platform, providing drug discovery services across diverse molecular modalities. Leveraging its fully integrated, end-to-end CRDMO enabling platform, WuXi AppTec supports global partners in translating frontier science into clinical reality.

From Visionary Idea to Industry Cornerstone

In 1992, Professor Richard Lerner, founding president of The Scripps Research Institute, and Nobel laureate Sydney Brenner published a paper that was far ahead of its time. Decades later, the concept they proposed has become a driving force reshaping how drugs are discovered.

The problem they sought to address was a longstanding bottleneck in pharmaceutical R&D.

At the early stages of drug discovery, scientists face a vast “ocean” of molecules, often numbering in the billions. The challenge is clear: how to retrieve the molecule capable of precisely engaging a disease target from such an immense molecular ocean?

Traditional screening approaches are time-consuming. Yet in the race against disease, time is a luxury.

Against this backdrop, Lerner and Brenner introduced the concept of DNA-encoded libraries (DEL).

In DEL technology, each small molecule is tagged with a unique DNA sequence that serves as a barcode, encoding the information of the compound.When billions of DNA-tagged compounds are incubated with a target protein, a silent competition unfolds. Only those molecules that bind tightly are retained, while others are washed away.

Instead of characterizing each compound’s structure individually, researchers simply read the attached tags. In this way, high-affinity "hit" compounds are revealed with remarkable speed and precision, ready to proceed to subsequent validation and optimization.

Over the past decade, advances in enabling technologies have propelled DEL into mainstream drug discovery.Today, DEL stands as a core tool in early discovery, enabling simultaneous screening of billions of molecules, making early drug discovery more efficient and cost-effective, and opening new avenues for targeting previously "undruggable" proteins.

Making DEL Technology Accessible

Just a few years ago, DEL was considered a "specialized technology" confined to a handful of advanced laboratories. For many biotech startups and academic groups, the cost and technical barriers placed the technology out of reach.

A key question emerged:Could this sophisticated technology be transformed into an accessible tool for all innovators?

In 2018, WuXi Biology (WuXi AppTec’s biology discovery platform) began building its DEL platform from scratch. Within months, its first DEL offering took shape; one year later, the platform welcomed its first client, embarking on its journey to enable partners worldwide.

Over time, the DEL platform has launched various DEL products, including DELopen, DELight, and DELpro, catering to the diverse needs of academic and industrial clients. Even a two-scientist startup can now leverage these capabilities to initiate innovative drug discovery.

“Our goal was to make DEL simple enough that any scientist—chemist or biologist, startup or large pharma—could use it easily,”said Dr. Letian Kuai, Vice President, Chief Scientific Officer of WuXi Biology, describing the original vision behind the platform.

Real-world stories often speak louder than concepts.

In one partnership, a major pharmaceutical company approached WuXi AppTec with a highly challenging target. The task was to identify compounds with strong binding affinity, which seemed nearly impossible.

Several months later, the DEL campaign delivered results. The team in WuXi AppTec identified molecules with affinity at the picomolar level, signifying an exceptionally tight binding interaction and enhanced potential for drug development.

This challenging task marked the foundation for a long-term partnership. The client subsequently initiated more than ten additional collaborations, advancing multiple programs against undruggable targets.

Image source: 123RF

Trust, built step by step.

Today, WuXi Biology conducts hundreds of DEL screenings annually, evaluating billions of compounds across therapeutic areas such as oncology and neuroscience. DEL has become an important cornerstone of its integrated drug discovery system.

Expanding Chemical Space of DEL

As screening capacity has scaled, a new challenge has emerged: how to further expand the molecular diversity and chemical space represented within DEL libraries.

In drug discovery, the cyclic scaffolds embedded in small molecules often determine their biological activity. If key bioactive scaffolds are absent from a DEL library, even the largest screening effort may fail to uncover the most promising candidates.

Therefore, expanding DEL chemical space by enriching libraries with structurally diverse, drug-like scaffolds has become a strategic focus for WuXi Biology.

In a 2025 study, the team focused on two important cyclic scaffolds: isoxazoline and isoxazole.

These motifs frequently appear in bioactive small molecules. For instance, isoxazoles are found in certain components of β-lactam antibiotics with antibacterial and antifungal properties, as well as in some analgesic and anti-inflammatory drugs.

Incorporating such privileged scaffolds into DEL libraries can significantly enhance the likelihood of identifying drug-like hits.

Yet constructing these structures under DEL conditions is far from trivial.

DEL chemistry must be performed under conditions compatible with DNA, which is highly sensitive to heat and extreme pH. Consequently, many classical organic reactions cannot be directly applied.

Building these cyclic scaffolds requires achieving high conversion yields while ensuring the tag remains intact, which is a delicate balancing act.

In this study, the team in WuXi Biology began with readily accessible aldehydes. By designing and optimizing a synthetic route based on the Huisgen cycloaddition reaction, they ultimately achieved the efficient construction of isoxazole and isoxazoline rings while attached to DNA.

Crucially, the method demonstrated broad substrate compatibility. Various heterocyclic aldehydes and bifunctional aldehydes could participate in the reaction, generating target structures without compromising the integrity.

With each such advance, DEL chemical space expands, translating into an increased probability of drug discovery.

The Next Frontier of DEL

This study is just one example of WuXi AppTec’s ongoing commitment to enhance DEL capabilities.

As traditional small-molecule discovery matures, the wave of new modalities presents fresh challenges. Novel molecules such as mRNA therapeutics, peptides, molecular glues, and bispecific protein degraders demand more sophisticated screening strategies.

Take bispecific protein degraders like PROTACs? as an example. They need to simultaneously engage two targets: one ligand binds the target protein, while another binds an E3 ubiquitin ligase.

The screening complexity increases exponentially.

To address this challenge, WuXi Biology has constructed a proprietary DEL library containing over 4 billion bifunctional molecules.In parallel, the team developed a bifunctional one-bead-one-compound (OBOC) DEL platform.

Unlike traditional liquid-phase DEL where molecules are screened in mixture, OBOC-DEL immobilizes each compound on a separate microbead.

During screening, these beads are incubated with both the target protein and the E3 ligase. Only molecules capable of simultaneously binding both proteins to form a ternary complex are identified.

This approach retains the high-throughput advantages of conventional DEL while significantly improving the efficiency of identifying bispecific degrader candidates.

Building on OBOC-DEL, the team is further evolving from affinity-based screening to functional screening, assessing not only binding interactions but also direct modulation of protein activity and cellular function, thereby selecting candidates with inherent biological functionality.

DEL continues to evolve.

Through ongoing technological iteration, WuXi AppTec’s DEL platform is helping global innovators shorten the path from scientific hypothesis to clinical candidate, accelerating the translation of cutting-edge science into transformative therapies.

Identifying a promising molecule is only the beginning.

Within WuXi AppTec’s fully integrated, end-to-end CRDMO platform, these candidates can seamlessly progress through synthesis, structural optimization, and biological validation. A complete translational pathway is already in place.

Along this journey, every refinement in chemistry and every improvement in screening efficiency ultimately serves a single goal: bringing scientific breakthroughs to patients faster.

參考資料：

[1] Wang et al., (2025) DNA-Compatible Huisgen [3 + 2] Cycloaddition of In Situ Formed Nitrile Oxides with Alkenes or Alkynes to Synthesize Isoxazolines or Isoxazoles. The Journal of Organic Chemistry (2025). https://pubs.acs.org/doi/full/10.1021/acs.joc.5c00078

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