編者按：糖尿病是全球范圍內(nèi)最常見(jiàn)的代謝疾病之一。根據(jù)國(guó)際糖尿病聯(lián)盟（IDF）的報(bào)告，2024年每9秒就有1人因糖尿病死亡。近年來(lái)，糖尿病的靶向治療取得多項(xiàng)突破，其中基于胰高血糖素樣肽-1（GLP-1）信號(hào)通路開(kāi)發(fā)的創(chuàng)新療法已經(jīng)成為治療糖尿病的研發(fā)熱點(diǎn)之一，目前全球已有近100款GLP-1相關(guān)藥物或藥物組合進(jìn)入臨床開(kāi)發(fā)階段或上市，其中多肽療法仍是主流。在GLP-1藥物開(kāi)發(fā)熱潮到來(lái)之前，藥明康德旗下的WuXi TIDES早已圍繞多肽藥物建立了一體化CRDMO平臺(tái)，提供所有類型的多肽，包括線性、環(huán)狀和高度修飾的多肽，以及非天然氨基酸、連接子、毒素和多肽偶聯(lián)藥物的合成服務(wù)，支持從藥物發(fā)現(xiàn)、CMC開(kāi)發(fā)到商業(yè)化生產(chǎn)的各個(gè)階段，助力合作伙伴更高效地為患者提供新一代GLP-1療法。在世界糖尿病日到來(lái)之際，本文將與讀者回顧GLP-1療法用于治療糖尿病的發(fā)展歷程。

解開(kāi)GLP-1之謎

GLP-1藥物的歷史可以追溯到上世紀(jì)60年代，當(dāng)時(shí)，麻省總醫(yī)院（MGH）的Joel Habener博士團(tuán)隊(duì)發(fā)現(xiàn)并克隆了編碼胰高血糖素前體的基因，并發(fā)表論文顯示胰高血糖素是一個(gè)包含124個(gè)氨基酸的多肽前體的切割產(chǎn)物。然而，這個(gè)多肽前體不但包含胰高血糖素，還包含一段與其結(jié)構(gòu)相似的氨基酸序列。這段序列由37個(gè)氨基酸組成，后來(lái)被命名為胰高血糖素樣肽-1。

隨后，Daniel Drucker博士加入了Habener博士的實(shí)驗(yàn)室，并與同在MGH的Svetlana Mojsov博士合作，對(duì)GLP-1的作用機(jī)制展開(kāi)深入研究。他們發(fā)現(xiàn)，食物攝入后，腸道釋放的GLP-1不但增強(qiáng)胰島素分泌，還抑制胰高血糖素的釋放并減緩胃排空速度。Mojsov博士更確定了GLP-1的第7至第37個(gè)氨基酸的序列是其活性成分，合成了這一活性片段并且驗(yàn)證了它的功能。1987年，一項(xiàng)包含7名志愿者的臨床研究顯示，輸注GLP-1能夠提高血液胰島素水平并降低血糖。

與此同時(shí)，哥本哈根大學(xué)的Jens Juul Holst教授通過(guò)研究接受腸道手術(shù)的患者，獨(dú)立證實(shí)了GLP-1的存在及其降糖作用。這些科學(xué)家因?yàn)樵诎l(fā)現(xiàn)GLP-1方面的卓越貢獻(xiàn)已經(jīng)獲得多個(gè)獎(jiǎng)項(xiàng)的表彰，包括2024年拉斯克臨床醫(yī)學(xué)獎(jiǎng)和2025年發(fā)布的科學(xué)突破獎(jiǎng)。

▲Daniel J. Drucker、Joel Habener、Jens Juul Holst、Lotte Bjerre Knudsen和Svetlana Mojsov（從左至右）因?yàn)樵贕LP-1生物學(xué)和藥物開(kāi)發(fā)方面的貢獻(xiàn)而獲得生命科學(xué)突破獎(jiǎng)

雖然GLP-1為降低血糖提供了全新工具，但是將它開(kāi)發(fā)成為藥物卻面臨著巨大的挑戰(zhàn)。這是因?yàn)镚LP-1在體內(nèi)的半衰期僅有幾分鐘，極易被二肽基肽酶-4（DPP-4）降解和被腎臟排出。因此，如何提高GLP-1的穩(wěn)定性成為藥物研發(fā)人員開(kāi)發(fā)的重要方向。意想不到的是，首款獲批GLP-1藥物的成功關(guān)鍵，竟是源于一個(gè)在蜥蜴毒液中的意外發(fā)現(xiàn)……

來(lái)自蜥蜴毒液的突破

20世紀(jì)80年代，在科學(xué)家們研究人類GLP-1的同時(shí)，美國(guó)國(guó)立衛(wèi)生研究院（NIH）的Jean-Pierre Raufman博士和John Pisano博士也在研究多肽激素。他們的研究方向是從動(dòng)物毒液中尋找能夠刺激胰島細(xì)胞的激素，而效果最好的毒液來(lái)自稱為希拉毒蜥（Gila monster）的蜥蜴。Raufman博士后來(lái)與內(nèi)分泌學(xué)家John Eng博士合作，發(fā)現(xiàn)了希拉毒蜥毒液中刺激胰島細(xì)胞的激素，將它們命名為exendin-3和exendin-4。

Eng博士敏銳地覺(jué)察到exendin-4可能成為一種治療糖尿病的新方式，因?yàn)樗cGLP-1非常類似。人類GLP-1在血液中的半衰期只有幾分鐘，而exendin-4的半衰期則長(zhǎng)達(dá)幾個(gè)小時(shí)，因此具備更好的成藥潛力。1996年，Eng博士在美國(guó)糖尿病協(xié)會(huì)年會(huì)上遇到了Amylin Pharmaceuticals公司的Andrew Young博士。Amylin公司當(dāng)時(shí)正在開(kāi)發(fā)糖尿病療法，看到exendin-4的研究后，Young博士覺(jué)得這是治療糖尿病的一個(gè)新策略，不妨一試。這促成了雙方的合作，Eng博士也將exendin-4的開(kāi)發(fā)權(quán)益授權(quán)給Amylin公司。

▲艾塞那肽的分子結(jié)構(gòu)（圖片來(lái)源：PubChem）

Amylin人工合成了exendin-4的類似物艾塞那肽（exenatide），隨后的臨床試驗(yàn)顯示，這種新藥不但顯著降低血糖水平，而且相比胰島素，更能減少患者發(fā)生低血糖的風(fēng)險(xiǎn)。這些在真實(shí)世界中取得的結(jié)果贏得了大藥企的青睞。2002年，禮來(lái)（Eli Lilly and Company）與Amylin達(dá)成3.25億美元合作，共同開(kāi)發(fā)艾塞那肽。它在2005年4月28日獲FDA批準(zhǔn)（商品名Byetta）用于治療2型糖尿病。

Byetta的獲批是GLP-1藥物開(kāi)發(fā)歷史上的重要里程碑，然而這款藥物也存在進(jìn)一步優(yōu)化的空間：患者通常每天需要注射兩次，使用不夠便利。同時(shí)，由于它與人類GLP-1之間的差異較大，部分患者會(huì)產(chǎn)生免疫反應(yīng)，產(chǎn)生的抗體進(jìn)而降低藥物療效。因此，研發(fā)人員也在探索其它方法來(lái)提高GLP-1藥物的穩(wěn)定性。

更高效、持久、便捷的GLP-1藥物

在艾塞那肽開(kāi)發(fā)的同時(shí)，諾和諾德（Novo Nordisk）的科學(xué)家們也在積極探索優(yōu)化人類GLP-1穩(wěn)定性的策略。最初的探索并不順利——經(jīng)過(guò)了一年多的嘗試，GLP-1多肽鏈的主干半衰期只從2分鐘提高到了5分鐘。最終，Lotte Bjerre Knudsen女士率領(lǐng)的團(tuán)隊(duì)使用脂肪酸側(cè)鏈對(duì)GLP-1進(jìn)行修飾，促進(jìn)了GLP-1與血液中白蛋白（albumin）的可逆結(jié)合。這種創(chuàng)新策略不僅保護(hù)GLP-1免于被DPP-4降解，還延緩了GLP-1在腎臟中的排出。這一系列改造帶來(lái)了利拉魯肽（liraglutide），它在2010年獲得FDA批準(zhǔn)（商品名Victoza），是一款每日注射一次的GLP-1受體激動(dòng)劑，其在血漿中的半衰期達(dá)到13個(gè)小時(shí)。

其它延長(zhǎng)GLP-1受體激動(dòng)劑半衰期的策略包括將藥物封裝在可以被生物降解的緩釋微球中（每周一次的艾塞那肽），該療法在2012年獲FDA批準(zhǔn)，商品名為Bydureon。將GLP-1多肽與抗體Fc片段融合生成的度拉魯肽（dulaglutide），和與白蛋白融合構(gòu)建的阿必魯肽（albiglutide）均在2014年獲批治療糖尿病，商品名分別為Trulicity和Tanzeum。

在利拉魯肽基礎(chǔ)上，Knudsen女士的團(tuán)隊(duì)進(jìn)一步優(yōu)化了脂肪酸側(cè)鏈的設(shè)計(jì)，并且將GLP-1多肽中第8位的丙氨酸替換成α-氨基異丁酸。這一系列改良形成了司美格魯肽（semaglutide），在保持GLP-1與受體結(jié)合親和力的同時(shí)，更有效抵抗了DPP-4的降解，將半衰期延長(zhǎng)至165個(gè)小時(shí)。它在2017年獲得FDA批準(zhǔn)治療2型糖尿?。ㄉ唐访鸒zempic），患者只需每周接受一次注射。

▲長(zhǎng)效GLP-1受體激動(dòng)劑結(jié)構(gòu)比較（圖片來(lái)源：參考資料[4]）

注射型司美格魯肽獲批不到兩年后，口服司美格魯肽（商品名Rybelsus）也成功獲得FDA的批準(zhǔn)上市治療2型糖尿病。Rybelsus創(chuàng)新地將司美格魯肽與一種名為SNAC的小分子吸收增強(qiáng)劑結(jié)合，使藥物更有效地在胃部被吸收，同時(shí)避免被胃中的肽酶降解。這一突破性口服GLP-1藥物，極大地提高了患者的用藥便捷性。

2022年，禮來(lái)公司的替爾泊肽（tirzepatide，商品名Mounjaro）獲FDA批準(zhǔn)治療2型糖尿病，它是一款葡萄糖依賴性促胰島素多肽（GIP）和GLP-1受體雙重激動(dòng)劑，旨在通過(guò)同時(shí)激活兩條腸促胰島素通路改善血糖控制。

GLP-1藥物的發(fā)展方向

在治療2型糖尿病之外，近10年來(lái)GLP-1藥物還多次獲批擴(kuò)展適應(yīng)癥，在治療肥胖癥、阻塞性睡眠障礙、代謝功能障礙相關(guān)性脂肪性肝炎等疾病方面也表現(xiàn)出顯著療效。研究人員還在臨床試驗(yàn)中探索GLP-1藥物治療神經(jīng)退行性疾病、慢性腎病、高血壓、銀屑病關(guān)節(jié)炎等多種疾病的療效。

研究人員也在探索進(jìn)一步提高GLP-1藥物療效、安全性和便捷性的手段。其中一個(gè)重要研發(fā)方向是將GLP-1受體激動(dòng)劑與靶向其它代謝相關(guān)通路的藥物聯(lián)合構(gòu)成組合療法，或在同一分子中靶向GLP-1受體和其它信號(hào)通路。已經(jīng)獲批的替爾泊肽就是一個(gè)范例。目前的在研療法在靶向GLP-1信號(hào)通路之外，還可同時(shí)靶向胰高血糖素受體（GCGR）、腸淀素受體、葡萄糖依賴性促胰島素多肽受體或降鈣素受體等不同受體介導(dǎo)的信號(hào)通路。

多家公司正在推進(jìn)口服GLP-1藥物開(kāi)發(fā)，以進(jìn)一步提升患者用藥便捷性。這一研發(fā)方向上的一個(gè)策略是開(kāi)發(fā)注射型GLP-1藥物的口服劑型，諾和諾德的Rybelsus代表著這一策略的重要突破。而另一個(gè)策略是開(kāi)發(fā)GLP-1受體的口服小分子激動(dòng)劑，目前多款小分子GLP-1受體激動(dòng)劑已經(jīng)在臨床試驗(yàn)中表現(xiàn)出積極的療效。提高患者用藥便捷性的另一個(gè)方向是開(kāi)發(fā)長(zhǎng)效GLP-1藥物，減少患者需要接受注射的次數(shù)。目前多款長(zhǎng)效GLP-1藥物在臨床試驗(yàn)中只需每月一次或更低頻率的注射就能夠維持療效。

▲處于臨床開(kāi)發(fā)階段的新一代GLP-1藥物（圖片來(lái)源：參考資料[1]）

藥明康德很高興能夠?yàn)槎嗫頖LP-1藥物賦能。在今年9月舉辦的藥明康德投資者開(kāi)放日活動(dòng)上公布的數(shù)據(jù)顯示，全球有近百款GLP-1受體激動(dòng)劑處于臨床試驗(yàn)階段或已上市，其中23款由藥明康德化學(xué)業(yè)務(wù)平臺(tái)支持，包括11款多肽類候選藥物和11款小分子候選藥物。展望未來(lái)，藥明康德將繼續(xù)秉持“讓天下沒(méi)有難做的藥，難治的病”的愿景，依托全球研發(fā)基地與生產(chǎn)網(wǎng)絡(luò)，憑借獨(dú)特的一體化、端到端CRDMO模式，持續(xù)推動(dòng)新一代GLP-1藥物的開(kāi)發(fā)進(jìn)程，造福全球患者。

在世界糖尿病日到來(lái)之際，我們?cè)僖淮握J(rèn)識(shí)到，糖尿病治療不只是控制血糖，更關(guān)乎生活質(zhì)量、長(zhǎng)期并發(fā)癥風(fēng)險(xiǎn)與公共健康負(fù)擔(dān)的系統(tǒng)性改善。GLP-1療法的演變，是生物醫(yī)學(xué)創(chuàng)新如何在疾病層面產(chǎn)生持續(xù)影響的一個(gè)縮影。期待隨著全球研發(fā)的進(jìn)展，GLP-1藥物及其它療法的持續(xù)推進(jìn)，人類更接近“讓糖尿病可以被更好管理和延緩，甚至逆轉(zhuǎn)”的長(zhǎng)期目標(biāo)。

CRDMO: Advancing Diabetes Care, The Scientific Journey and Future of GLP-1 Therapeutics

Diabetes is one of the most common metabolic diseases worldwide. According to the International Diabetes Federation (IDF), every nine seconds in 2024, someone dies as a result of this disease. In recent years, targeted therapies for diabetes have made significant progress, particularly those developed based on the glucagon-like peptide-1 (GLP-1) signaling pathway, which has become a central focus of therapeutic research. About 100 GLP-1–related drugs or drug combinations are currently in clinical development or have been approved worldwide, with peptide-based therapies continuing to represent the major therapeutic modality.

WuXi TIDES, an integral part of WuXi AppTec, has built an integrated CRDMO platform focused on peptides. The platform offers high-throughput library synthesis and custom peptide synthesis, supporting a wide range of peptides, including linear, cyclic, and highly modified peptides, unnatural amino acids (UAAs), linkers, toxins and peptide conjugates. WuXi TIDES simplifies peptide drug development by providing discovery, CMC development, and the entire manufacturing supply chain under one roof. WuXi TIDES enables partners to accelerate the development and delivery of next-generation GLP-1 therapies to patients. In recognition of World Diabetes Day, this article reviews the scientific and clinical progress of GLP-1 therapies in diabetes treatment.

Unraveling the GLP-1 Mystery

The origins of GLP-1 research date back to the 1960s, when Dr. Joel Habener’s team at Massachusetts General Hospital (MGH) discovered and cloned the gene encoding proglucagon.They demonstrated that glucagon is derived from a 124–amino acid polypeptide precursor, which also contains an additional 37–amino acid sequence. This sequence was later identified as glucagon-like peptide-1 (GLP-1).

Dr. Daniel Drucker joined Dr. Habener’s laboratory and, together with Dr. Svetlana Mojsov at MGH, carried out seminal work that elucidated GLP-1’s mechanism of action. They found that GLP-1 released from the intestine after food intake enhances insulin secretion, suppresses glucagon release, and slows gastric emptying. Dr. Mojsov further pinpointed that the 7–37 amino acid fragment constitutes the biologically active form of GLP-1, synthesized the peptide and confirmed its activity experimentally.

Clinical evidence soon followed. In 1987, a study involving seven volunteers demonstrated that GLP-1 infusion increased circulating insulin levels while lowering blood glucose. Around the same time, Professor Jens Juul Holst at the University of Copenhagen independently confirmed the existence and glucose-lowering effects of GLP-1 through observations in patients who had undergone intestinal surgery. For their foundational contributions to GLP-1 biology and drug development, these scientists were recognized with major awards, including the 2024 Lasker Clinical Medical Research Award and the 2025 Breakthrough Prize in Life Sciences.

A Breakthrough from Lizard Venom

Although GLP-1 introduced an entirely new therapeutic mechanism, transforming it directly into a drug proved challenging due to its extremely short half-life of only a few minutes, resulting in rapid degradation by DPP-4 and clearance by the kidneys. The search for more stable analogs took an unexpected turn in the 1980s, when Dr. Jean-Pierre Raufman and Dr. John Pisano at the U.S. National Institutes of Health (NIH) began studying peptide hormones from animal venom. They observed that venom from the Gila monster strongly stimulated pancreatic islet cells. Working with endocrinologist Dr. John Eng, they identified two peptides, exendin-3 and exendin-4.

Dr. Eng realized that exendin-4’s strong structural similarity to GLP-1, combined with its significantly longer half-life of several hours, made it a highly promising therapeutic candidate. In 1996, he met Dr. Andrew Young of Amylin Pharmaceuticals at the American Diabetes Association Annual Meeting, which led Amylin to license exendin-4 and develop its synthetic analog, exenatide. Clinical trials showed that exenatide effectively reduced blood glucose while also lowering the risk of hypoglycemia compared with insulin. Eli Lilly and Company entered a $325 million partnership with Amylin in 2002, andon April 28, 2005, exenatide (brand name Byetta) was approved by the FDA for the treatment of type 2 diabetes.

Although Byetta marked a major milestone, its twice-daily injection schedule and potential immunogenicity prompted continued efforts to develop longer-acting and more convenient GLP-1 therapies.

Toward Longer-Acting and More Convenient GLP-1 Therapies

At Novo Nordisk, researchers sought to enhance GLP-1 stability using structural modification strategies. After extensive work, they introduced a fatty acid side chain enabling reversible binding to serum albumin, thereby protecting the molecule from enzymatic degradation and slowing renal clearance. This innovation led to liraglutide (Victoza), which was approved in 2010. Its extended half-life enabled once-daily dosing.

Additional approaches soon followed. A biodegradable microsphere formulation of exenatide, enabling once-weekly administration, was approved in 2012 as Bydureon. Dulaglutide (Trulicity), which fuses GLP-1 to an Fc antibody fragment, and albiglutide (Tanzeum), which fuses GLP-1 to albumin, were both approved in 2014.

Building on liraglutide, researchers optimized the lipid side chain and substituted the amino acid at position 8 with α-aminoisobutyric acid to create semaglutide (Ozempic). With a half-life of approximately 165 hours, semaglutide enabled once-weekly dosing and was approved in 2017. Two years later, oral semaglutide (Rybelsus) was approved, using the absorption enhancer SNAC to promote gastric uptake. In 2022, Eli Lilly’s tirzepatide (Mounjaro), a dual GIP/GLP-1 receptor agonist, was approved for type 2 diabetes.

Future Directions in GLP-1 Therapeutics

Beyond type 2 diabetes, GLP-1 therapies have demonstrated efficacy in obesity, obstructive sleep apnea, and metabolic dysfunction–associated steatohepatitis (MASH), with ongoing clinical trials exploring potential applications in neurodegenerative disease, chronic kidney disease, hypertension, and psoriatic arthritis. Research directions now include developing multi-receptor agonists that integrate GLP-1 signaling with pathways such as GIP and glucagon receptor signaling, advancing orally bioavailable GLP-1 receptor agonists, and designing long-acting formulations requiring administration only monthly or even less frequently.

According to data shared at WuXi AppTec’s Investor Day in September, nearly 100 GLP-1 receptor agonists are currently in clinical development or already on the market globally, with 23 supported by WuXi AppTec’s chemistry platform, including 11 peptide candidates and 11 small-molecule candidates. Looking ahead, WuXi AppTec will continue to support the advancement of next-generation GLP-1 therapies through its unique integrated, end-to-end CRDMO platform, helping bring innovative therapeutic options to patients worldwide.

參考資料：

[1] Drucker (2025). GLP-1-based therapies for diabetes, obesity and beyond. Nature Reviews Drug Discovery, https://doi.org/10.1038/s41573-025-01183-8

[2] Diabetes global report 2000 — 2050. Retrieved October 29, 2025, from https://diabetesatlas.org/data-by-location/global/

[3] Zheng et al., (2024). Glucagon-like peptide-1 receptor: mechanisms and advances in therapy. Signal Transduction and Targeted Therapy, https://doi.org/10.1038/s41392-024-01931-z

[4] Andersen et al., (2018). Glucagon-like peptide 1 in health and disease. Nature Reviews Endocrinology, https://doi.org/10.1038/s41574-018-0016-2

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