从5步到仅1步，收率大幅提升，药明康德酶催化平台如何赋能新药研发？| Bilingual

几年前，药明康德子公司合全药业的酶催化团队接到一项关键工艺优化任务。

彼时，某客户正在推进一款创新药的研发，其中一个关键手性中间体沿用传统化学催化需要5步，总收率仅约为40%。随着项目向临床后期迈进，这条路线在效率与成本上的瓶颈日益凸现，优化迫在眉睫。

合全药业团队迅速行动，依托自有酶库展开筛选与开发，成功构建出一条生物催化新路线。令人振奋的是，新路线将原本需要5步的合成过程简化为1步，收率提高到76%，成本降低1/3。

但团队并未止步于此。由于初始方案仍需三种酶与两种辅酶协同作用，操作复杂度仍有优化空间。为此，团队进一步引入高通量定向进化技术，在一个月内对酶进行两轮定向进化。最终，反应体系被简化为仅需一种酶与一种辅酶，合成时间缩短2周，收率跃升至90%，相较最初五步化学路线，总成本降低了70%以上，为这款药物的商业化进程扫清了障碍。

从“五步收率40%”到“一步收率90%”，跃升的远不止数字，更推动了客户药物分子的研发进程提速。这一案例，也成为多年来药明康德酶催化平台能力建设和赋能客户的经典缩影。

耕耘十余载，酶催化一体化平台赋能新药工艺开发和生产

故事要从更早说起。

上世纪，工业界便开始探索将酶用于化合物合成催化。随着酶催化及酶定向进化技术的跨越式发展，进入21世纪，这一技术成为制药工艺开发领域的重要手段。

酶不仅能催化合成多种天然与非天然化合物，而且反应条件温和，通常在近水相环境中进行，避免了传统化学合成中常见的高温、高压条件。这使得酶催化技术被视为绿色化学的重要组成部分，正推动药物合成朝着更高效、更可持续的方向变革。

作为全球医药创新的赋能者，药明康德于2012年开始启动酶催化技术的系统性布局。最初的工作朴实而扎实：收集天然酶和商业化酶，建立筛选酶库，以支持原料药工艺开发。

那时候，团队没有经验，也没有专业的实验室，一切从零开始。团队从市场上买酶，就放在几台冰箱里，一步一步摸索着往前走。

很快，团队成功将酶催化工艺应用于一项商业化生产交付，迈出了从零到一的关键一步。随着经验不断积累，客户的需求也日益增多。

然而，行业需求持续攀升的同时，一个根本性瓶颈也逐渐显现——天然酶在催化非天然化合物合成时，往往活性不佳，极大限制了其广泛应用。

伴随酶定向进化技术的日趋成熟，药明康德敏锐把握这一趋势，于2016年迅速筹建专用的酶进化实验室，引入高通量筛选技术与半理性设计，构建起自主的酶定向进化能力，实现了从“被动选酶”到“主动进化酶”的关键跃升。

▲高通量酶进化设备

2017年，公司首个中试500L发酵罐投用，标志着酶发酵制备从实验室规模迈入中试放大阶段。随着需求不断增长，团队持续扩建、提升酶产能，规模化生产能力显著增强。与此同时，总面积近千平方米的两个酶定向进化实验中心也相继投入运营，进一步增强了酶突变体筛选与功能评价的能力，为酶催化技术的系统化应用提供了坚实支撑。

经过十多年的持续投入，该平台已建立起系统化的完整能力——一个覆盖酶筛选、酶进化、酶发酵、酶工艺开发与放大的一体化平台。

在酶筛选环节，自有酶库涵盖超过3500种生产用酶及超过20万个优质突变体，可有力支持对目标化合物的快速筛选。平均两周之内，团队就能完成对一个化合物的酶筛选。

酶催化平台同时能做40多个酶催化项目。若初始筛选获得的酶在活性或选择性上仍需提升，平台通过高通量定向进化，快速开发出高选择性、高反应效率的酶突变体。

目标酶确定后，平台具备规模化制备酶粉的能力。发酵车间从实验室规模到10,000 L反应釜实现无缝衔接，超20,000 L的总发酵容量可同时满足从公斤级到吨级的酶快速交付，为处于不同阶段的项目的工艺开发与生产提供支持。

十余年来，平台已累计开发了650个酶催化工艺，并完成440个生产项目的交付，其中包括20项处于临床III期及商业化阶段的项目。据统计，平台累计交付的关键手性中间体和原料药已超过500吨。

在某个早期项目中，客户面临一道严峻的工艺瓶颈：原有的酶催化反应体系体积高达500V、酶用量需达3X（相比于底物量），转化率却仅为40%；而另一条化学合成路线虽可替代，但工艺复杂，难以支持公斤级原料药的生产。

面对这一困局，接手项目后，酶催化团队直击源头——对酶本身进行定向改造。经过五轮连续的定向进化，团队获得了性能显著提升的新酶，并将新工艺的反应体积大幅缩减至80V，下降了超6倍；酶用量也显著降低至0.1X。基于这一突破，团队顺利完成了数十公斤关键手性中间体的生产，为客户临床试验的快速推进提供了坚实支持。

▲药明康德酶发酵车间

酶催化：在新兴药物浪潮中破局

如今，药明康德酶催化平台正被用于应对不同分子类型所带来的合成挑战。

近年来，多肽与寡核苷酸药物不断拓展疾病治疗的边界，成为新药研发领域的一股新浪潮。据统计，全球已有约100款多肽药物获批上市，超过40款多肽新药是在过去十年间获得FDA批准的。与此同时，寡核苷酸药物的应用范围也从罕见病逐步拓展至更广泛的疾病领域。

这波浪潮对合成技术提出了新的挑战：更长的序列、更复杂的修饰、更严格的质量控制，以及更紧迫的交付周期。

面对这一趋势，药明康德的酶催化一体化平台已建立起针对性的解决方案。

在多肽领域，团队针对各类新型非天然氨基酸进行酶催化方法开发，进一步优化合成路线，减少有机溶剂的使用，加速多肽药物的研发和生产进程，同时实现绿色生产。

以某早期开发阶段的多肽项目为例，采用传统化学合成路线需经历三十余步反应，总收率不足1%。当项目进入关键的工艺性能确认（PPQ）阶段后，效率瓶颈亟待突破。在此背景下，酶催化方案被提上议程。团队与客户紧密合作，对整条合成路线进行系统性重构，定向进化了十余种酶，最终使合成步骤减少了十余步，总收率提升了数十倍，为该药物的规模化生产提供了关键支持。

在寡核苷酸领域，长链RNA的制备一直是这类药物开发中的技术难点，传统固相合成在纯度与收率方面均面临挑战。为解决这一问题，药明康德酶催化团队采用酶促连接策略：根据RNA的二级结构设计连接位点，开发高活性连接酶，将多个短链RNA片段拼接成长链。该方法精准高效地突破了长链RNA片段的制备瓶颈。基于此工艺，团队已成功将其应用于复杂的双链siRNA-GalNAc偶联分子中，酶连接效率超过95%，粗品纯度高达98%，且总体收率显著提升。

如今，药明康德的酶催化平台正成为多肽和寡核苷酸等新兴分子药物研发的关键加速器之一，持续赋能客户突破工艺开发和生产瓶颈，提升研发效率。酶催化与化学合成的协同效应，正在创新分子的浪潮中释放出更大的赋能潜力。

与此同时，随着酶定向进化技术与其他技术的不断融合，酶分子的改造效率有望进一步提升，应用边界也将持续拓宽。可以预见，这一技术未来将在更多类型的化学反应中得到应用，不仅助力提升药物研发和生产效率，也为推动行业的绿色可持续发展提供重要支持。作为药明康德的内部赋能平台之一，酶催化代表了一条更高效、也更绿色的合成路径。

从实验室研究到用于商业化生产，从筛选单个酶分子到稳定交付数十吨关键原料，药明康德酶催化平台的能力不断跃升，但那份初心始终未改——赋能客户，加速项目进程，助力客户将新疗法更快惠及病患。

不止于酶：一体化平台的技术网络协同

在药明康德一体化的CRDMO赋能平台中，酶催化是众多技术平台中的一员，其发展是公司全面技术和能力不断建设、优化迭代的重要体现。它与流动化学、金属催化、结晶及颗粒工程等在内的各类技术能力互为补充，共同构成了一张精密协同的能力网络，为客户项目提供全面、多维度的工艺开发和生产解决方案。

例如，酶催化与流动化学常被誉为绿色化学的“两大顶流”——一个用生物催化替代苛刻的化学条件，一个用连续化生产工艺提升效率与安全性。在药明康德一体化平台上，这些技术的协同应用，旨在为客户提供从实验室工艺开发到商业化生产交付的全链条支持。

而这张技术网络的底层逻辑始终如一：把复杂的底层技术，转化为可高效、高质量交付的赋能服务，持续支持全球创新者加速新药研发进程。客户不需要精通酶定向进化的计算逻辑，也不需要理解发酵罐的参数控制——他们只需要看到一个更高效、更稳定、更经济的合成方案。

真正的赋能价值，往往藏在那些看不见的地方：藏在一轮又一轮的突变体筛选中，藏在完成酶蛋白合成的发酵罐中，藏在一次又一次的酶用量优化中，藏在不断迭代优化的合成路线里。每一次按时交付、每一次工艺突破——它们或许不会出现在新药获批的新闻标题里，却累积成药明康德团队可验证的信誉，沉淀在每一款加速问世的创新药物背后。

这或许正是赋能的意义：不站在聚光灯下，却让光更快地抵达需要的人。

From Five Steps to One: How WuXi AppTec's Biocatalysis Platform Enables Drug Innovation

Several years ago, WuXi STA, a subsidiary of WuXi AppTec, undertook a process optimization assignment for a client.

At the time, the client was advancing the development of an innovative drug candidate. A key chiral intermediate in the process required five steps using traditional chemical route, with an overall yield of approximately 40%. As the project moved toward later clinical stages, efficiency and cost constraints of this route became more evident, prompting a need for optimization.

WuXi STA’s biocatalysis team proposed an enzymatic route, condensing the original five-step synthesis into a single step, increasing the yield to 76%, and lowering costs by one-third.

The team did not stop there. The initial approach still required the coordinated action of three enzymes and two coenzymes, and operational complexity was an opportunity for improvement. To address this issue, the team leveraged high throughput directed evolution technology, targeting key regions and performing two rounds of directed evolution on the enzyme within a month. 

Ultimately, the resulting reaction system was simplified to only one enzyme and one coenzyme. Synthesis time was reduced by two weeks, yield increased to 90%, and total cost was reduced by more than 70% compared to the original five-step chemical route – clearing a major hurdle for the drug's path toward commercialization.

From "five steps, 40% yield" to "one step, 90% yield", the leap was far more than a numerical – it accelerated the client's overall drug molecule development timeline. This case illustrates the capabilities of WuXi AppTec's biocatalysis platform and the value it has delivered to clients over the years.

Over a Decade of Cultivation: An Integrated Biocatalysis Platform Enables Drug Process Development and Manufacturing

The story begins earlier.

In the last century, the industry began exploring the use of enzymes to catalyze the synthesis of chemical compounds. With major advances in biocatalysis and directed evolution technology, by the 21st century this approach had become an important tool in pharmaceutical process development.

Enzymes can catalyze the synthesis of a wide range of both natural and unnatural compounds. They operate under mild conditions, typically in near-aqueous environments, avoiding the high temperatures and high pressures common in traditional chemical synthesis. As a result, biocatalysis is regarded as a cornerstone of green chemistry and is driving a shift toward more efficient and sustainable drug synthesis.

WuXi AppTec began systematically building its biocatalysis capabilities in 2012. The initial work was foundational: collecting natural and commercial enzymes to establish a screening enzyme library that would support active pharmaceutical ingredient (API) process development.

Back then, the team had no prior experience and no dedicated laboratory – and started from scratch. Buying enzymes from the market, the team stored them in a few refrigerators, and moved forward step by step. 

Soon, the team successfully applied a biocatalysis process to a commercial manufacturing delivery — a crucial step from zero to one. As experience grew and expertise deepened, client demands grew steadily. 

However, even as industry demand continued to rise, a fundamental bottleneck emerged: natural enzymes often exhibited poor activity when catalyzing the synthesis of unnatural compounds, severely limiting broader application.

With the increasing maturity of directed evolution technology, WuXi AppTec moved decisively. In 2016, it established a dedicated enzyme evolution laboratory, introducing high-throughput screening and semi-rational design to build in-house directed evolution capabilities. This marked a transition from passive enzyme screening to active enzyme engineering.

▲High Throughput Evolution Robot

In 2017, the company's first 500 L pilot-scale fermenter came online, signaling the transition of enzyme fermentation preparation from laboratory scale to pilot scale. 

To meet steadily increasing demand, the team expanded and upgraded enzyme production capacity, significantly strengthening large-scale manufacturing capabilities. Meanwhile, two directed evolution laboratories spanning nearly a thousand square meters were put into operation, further enhancing the ability to screen enzyme variants and evaluate function, providing solid support for the systematic application of biocatalysis technology.

After more than a decade of sustained investment, the platform has established comprehensive, systematic capabilities – an integrated platform covering enzyme screening, enzyme evolution, enzyme fermentation, and enzyme process development and scale-up. 

In enzyme screening, the in-house enzyme library contains over 3,500 manufacturing-grade enzymes and more than 200,000 optimized variants, enabling rapid screening against target compounds. On average, the team can complete enzyme screening for a compound within two weeks. 

If the initially screened enzyme requires further improvement in activity or selectivity, the platform can run more than 40 enzyme evolution projects in parallel. Using the high-throughput screening laboratory, the team quickly identifies enzyme variants with high selectivity and reaction efficiency for each project. 

Once the target enzyme is identified, the platform possesses the capability for large-scale enzyme powder manufacturing. The fermentation facility seamlessly connects laboratory-scale to 10,000-liter reactors, with total fermentation capacity exceeding 20,000 liters. This allows for rapid delivery of enzymes at scales ranging from kilograms to metric tons, fulfilling project requirements at every stage.

For more than a decade, our platform has developed 650 enzyme-catalyzed processes and completed delivery of 440 manufacturing projects, including 20 projects in Phase III clinical or commercial stages. To date, the platform has delivered over 500 metric tons of key chiral intermediates and APIs. 

In one early-stage project, a client faced a severe process bottleneck: the existing enzyme-catalyzed reaction system required a volume of 500V and an enzyme loading of 3X (relative to the substrate) yet achieved only 40% conversion. An alternative chemical synthesis route existed, but its complexity made kilogram-scale API manufacturing impractical.

Confronted with this impasse, the team addressed the root cause – engineering the enzyme itself. After five consecutive rounds of directed evolution, the team obtained a new enzyme with significantly improved performance. The new process reduced the reaction volume to 80V, and enzyme loading was reduced to 0.1X. Based on these results, the team successfully manufactured dozens of kilograms of the key chiral intermediate, providing robust support for the client's rapid clinical trial advancement.

▲Fermentation Plant at WuXi AppTec

Biocatalysis: Navigating the Wave of Emerging Modalities

Today, WuXi AppTec's biocatalysis platform is being deployed to address synthesis challenges posed by diverse molecular modalities. 

In recent years, peptide and oligonucleotide drugs have continuously expanded the frontiers of disease treatment, emerging as a new wave in drug innovation. Approximately 100 peptide drugs have been approved globally, with over 40 novel peptides approved by the FDA in the past decade alone. Meanwhile, the application scope of oligonucleotide drugs is expanding from rare diseases to broader therapeutic areas.

This wave presents new challenges for synthesis technology: longer sequences, more complex modifications, stricter quality control, and tighter delivery timelines. In response, WuXi AppTec's integrated biocatalysis platform has established targeted solutions.

In the peptide field, the team has been developing enzyme-catalyzed methods for various novel unnatural amino acids (UAAs) to optimize synthesis and reduce organic solvent usage and expedite manufacturing of UAAs and peptide drugs. 

Take, for example, an early-stage peptide project where the traditional chemical synthesis route required over 30 steps, with a total yield below 1%. As the project entered the critical process performance qualification (PPQ) stage, overcoming this efficiency bottleneck became a priority. 

A biocatalysis solution was proposed. Working closely with the client, the team systematically re-engineered the entire synthetic route and performed directed evolution on more than ten enzymes. The result: the number of synthetic steps was reduced by more than ten, and the overall yield increased by several dozen-fold, providing substantial support for the drug's large-scale manufacturing.

In the oligonucleotide field, the preparation of long-chain RNA has long been a major pain point in drug development, with traditional solid-phase synthesis facing challenges in both poor purity and low yield. 

To address this, WuXi AppTec's biocatalysis team utilized an enzymatic ligation strategy to improve success rates in long RNA synthesis. They designed ligation sites based on RNA secondary structure, developed highly active ligases, and assembled multiple short RNA fragments into long chains. This approach addressed the key bottleneck in preparing long-chain RNA fragments. The team applied this process to a complex di siRNA–GalNAc conjugate, achieving enzymatic ligation efficiencies above 95%, crude product purity up to 98%, and a significantly improved final yield.

Today, the platform serves as one of the important accelerators for drug development of emerging modalities such as peptides and oligonucleotides, continuously enabling clients to overcome process development and manufacturing bottlenecks and improve efficiency. The synergy between biocatalysis and chemical synthesis is creating even greater enabling potential amid the wave of innovative molecules.

Meanwhile, as directed evolution technology increasingly integrates with other tools, the efficiency of enzyme engineering is expected to improve further, and the boundaries of application will continue to expand. This technology is expected to be applied to a broader range of chemical reactions in the future, supporting both drug development efficiency and the industry's progress toward greener and more sustainable practices. As one of WuXi AppTec's internal enabling platforms, biocatalysis represents a more efficient and greener synthetic pathway.

From laboratory research to commercial manufacturing, from screening a single enzyme molecule to stably delivering diverse fermentation products from kilograms to metric tons, the capabilities of WuXi AppTec's biocatalysis platform have grown steadily. Yet the founding purpose remains unchanged: to enable clients, accelerate project timelines, and help clients bring breakthrough therapies to patients faster. 

Beyond Enzymes: Synergy Across an Integrated Platform

Within WuXi AppTec's integrated CRDMO enabling platform, biocatalysis is a key component of its broader network of technology platforms. Its development reflects the company's ongoing capability building and iterative optimization across comprehensive technologies. It complements various other technical capabilities – such as flow chemistry, metal catalysis, crystallization and particle engineering among others – all of which together form a coordinated capability network. This network provides clients with comprehensive, multi-dimensional process development and manufacturing solutions.

Biocatalysis and flow chemistry, for example, are often considered as two pillars of green chemistry: biocatalysis enables reactions under mild, near-aqueous conditions, while flow chemistry improves efficiency and safety through continuous manufacturing. On WuXi AppTec's integrated platform, the synergistic application of these technologies aims to provide clients with full-chain support from laboratory process development to commercial manufacturing delivery.

The underlying logic of this technology network remains consistent: turning complex foundational technologies into reliable enabling services that support global innovators in accelerating new drug development. Clients don't need to master the computational logic of directed evolution or understand the parameter control of a fermenter. They just need to see a more efficient, robust, and economical synthetic solution.

The true value of enablement often lies in the unseen details: in round after round of variant screening, in the enzyme synthesized within fermenters, and in continuously optimized synthetic routes. Every on-time delivery, every process breakthrough – these may not appear in the headlines announcing a new drug’s approval, but they accumulate into the trust for the WuXi AppTec team and are embedded in therapies that reach patients faster.

Perhaps this is the true meaning of enabling: not standing in the spotlight, but helping the light reach those in need faster.

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