編者按：糖尿病是全球范圍內最常見的代謝疾病之一。根據國際糖尿病聯盟（IDF）的報告，2024年每9秒就有1人因糖尿病死亡。近年來，糖尿病的靶向治療取得多項突破，其中基于胰高血糖素樣肽-1（GLP-1）信號通路開發(fā)的創(chuàng)新療法已經成為治療糖尿病的研發(fā)熱點之一，目前全球已有近100款GLP-1相關藥物或藥物組合進入臨床開發(fā)階段或上市，其中多肽療法仍是主流。在GLP-1藥物開發(fā)熱潮到來之前，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，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、毒素和多肽偶聯藥物的合成服務，支持從藥物發(fā)現、CMC開發(fā)到商業(yè)化生產的各個階段，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GLP-1之謎

GLP-1藥物的歷史可以追溯到上世紀60年代，當時，麻省總醫(yī)院（MGH）的Joel Habener博士團隊發(fā)現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包含124個氨基酸的多肽前體的切割產物。然而，這個多肽前體不但包含胰高血糖素，還包含一段與其結構相似的氨基酸序列。這段序列由37個氨基酸組成，后來被命名為胰高血糖素樣肽-1。

隨后，Daniel Drucker博士加入了Habener博士的實驗室，并與同在MGH的Svetlana Mojsov博士合作，對GLP-1的作用機制展開深入研究。他們發(fā)現，食物攝入后，腸道釋放的GLP-1不但增強胰島素分泌，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個氨基酸的序列是其活性成分，合成了這一活性片段并且驗證了它的功能。1987年，一項包含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，哥本哈根大學的Jens Juul Holst教授通過研究接受腸道手術的患者，獨立證實了GLP-1的存在及其降糖作用。這些科學家因為在發(fā)現GLP-1方面的卓越貢獻已經獲得多個獎項的表彰，包括2024年拉斯克臨床醫(yī)學獎和2025年發(fā)布的科學突破獎。

▲Daniel J. Drucker、Joel Habener、Jens Juul Holst、Lotte Bjerre Knudsen和Svetlana Mojsov（從左至右）因為在GLP-1生物學和藥物開發(fā)方面的貢獻而獲得生命科學突破獎

雖然GLP-1為降低血糖提供了全新工具，但是將它開發(fā)成為藥物卻面臨著巨大的挑戰(zhàn)。這是因為GLP-1在體內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藥物的成功關鍵，竟是源于一個在蜥蜴毒液中的意外發(fā)現……

來自蜥蜴毒液的突破

20世紀80年代，在科學家們研究人類GLP-1的同時，美國國立衛(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物毒液中尋找能夠刺激胰島細胞的激素，而效果最好的毒液來自稱為希拉毒蜥（Gila monster）的蜥蜴。Raufman博士后來與內分泌學家John Eng博士合作，發(fā)現了希拉毒蜥毒液中刺激胰島細胞的激素，將它們命名為exendin-3和exendin-4。

Eng博士敏銳地覺察到exendin-4可能成為一種治療糖尿病的新方式，因為它與GLP-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的半衰期則長達幾個小時，因此具備更好的成藥潛力。1996年，Eng博士在美國糖尿病協會年會上遇到了Amylin Pharmaceuticals公司的Andrew Young博士。Amylin公司當時正在開發(fā)糖尿病療法，看到exendin-4的研究后，Young博士覺得這是治療糖尿病的一個新策略，不妨一試。這促成了雙方的合作，Eng博士也將exendin-4的開發(fā)權益授權給Amylin公司。

▲艾塞那肽的分子結構（圖片來源：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)生低血糖的風險。這些在真實世界中取得的結果贏得了大藥企的青睞。2002年，禮來（Eli Lilly and Company）與Amylin達成3.25億美元合作，共同開發(fā)艾塞那肽。它在2005年4月28日獲FDA批準（商品名Byetta）用于治療2型糖尿病。

Byetta的獲批是GLP-1藥物開發(fā)歷史上的重要里程碑，然而這款藥物也存在進一步優(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，由于它與人類GLP-1之間的差異較大，部分患者會產生免疫反應，產生的抗體進而降低藥物療效。因此，研發(fā)人員也在探索其它方法來提高GLP-1藥物的穩(wěn)定性。

更高效、持久、便捷的GLP-1藥物

在艾塞那肽開發(fā)的同時，諾和諾德（Novo Nordisk）的科學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——經過了一年多的嘗試，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女士率領的團隊使用脂肪酸側鏈對GLP-1進行修飾，促進了GLP-1與血液中白蛋白（albumin）的可逆結合。這種創(chuàng)新策略不僅保護GLP-1免于被DPP-4降解，還延緩了GLP-1在腎臟中的排出。這一系列改造帶來了利拉魯肽（liraglutide），它在2010年獲得FDA批準（商品名Victoza），是一款每日注射一次的GLP-1受體激動劑，其在血漿中的半衰期達到13個小時。

其它延長GLP-1受體激動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，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。

在利拉魯肽基礎上，Knudsen女士的團隊進一步優(yōu)化了脂肪酸側鏈的設計，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與受體結合親和力的同時，更有效抵抗了DPP-4的降解，將半衰期延長至165個小時。它在2017年獲得FDA批準治療2型糖尿?。ㄉ唐访鸒zempic），患者只需每周接受一次注射。

▲長效GLP-1受體激動劑結構比較（圖片來源：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的小分子吸收增強劑結合，使藥物更有效地在胃部被吸收，同時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，禮來公司的替爾泊肽（tirzepatide，商品名Mounjaro）獲FDA批準治療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受體雙重激動劑，旨在通過同時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GLP-1藥物還多次獲批擴展適應癥，在治療肥胖癥、阻塞性睡眠障礙、代謝功能障礙相關性脂肪性肝炎等疾病方面也表現出顯著療效。研究人員還在臨床試驗中探索GLP-1藥物治療神經退行性疾病、慢性腎病、高血壓、銀屑病關節(jié)炎等多種疾病的療效。

研究人員也在探索進一步提高GLP-1藥物療效、安全性和便捷性的手段。其中一個重要研發(fā)方向是將GLP-1受體激動劑與靶向其它代謝相關通路的藥物聯合構成組合療法，或在同一分子中靶向GLP-1受體和其它信號通路。已經獲批的替爾泊肽就是一個范例。目前的在研療法在靶向GLP-1信號通路之外，還可同時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的信號通路。

多家公司正在推進口服GLP-1藥物開發(fā)，以進一步提升患者用藥便捷性。這一研發(fā)方向上的一個策略是開發(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。而另一個策略是開發(fā)GLP-1受體的口服小分子激動劑，目前多款小分子GLP-1受體激動劑已經在臨床試驗中表現出積極的療效。提高患者用藥便捷性的另一個方向是開發(fā)長效GLP-1藥物，減少患者需要接受注射的次數。目前多款長效GLP-1藥物在臨床試驗中只需每月一次或更低頻率的注射就能夠維持療效。

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

藥明康德很高興能夠為多款GLP-1藥物賦能。在今年9月舉辦的藥明康德投資者開放日活動上公布的數據顯示，全球有近百款GLP-1受體激動劑處于臨床試驗階段或已上市，其中23款由藥明康德化學業(yè)務平臺支持，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，藥明康德將繼續(xù)秉持“讓天下沒有難做的藥，難治的病”的愿景，依托全球研發(fā)基地與生產網絡，憑借獨特的一體化、端到端CRDMO模式，持續(xù)推動新一代GLP-1藥物的開發(fā)進程，造福全球患者。

在世界糖尿病日到來之際，我們再一次認識到，糖尿病治療不只是控制血糖，更關乎生活質量、長期并發(fā)癥風險與公共健康負擔的系統性改善。GLP-1療法的演變，是生物醫(yī)學創(chuàng)新如何在疾病層面產生持續(xù)影響的一個縮影。期待隨著全球研發(fā)的進展，GLP-1藥物及其它療法的持續(xù)推進，人類更接近“讓糖尿病可以被更好管理和延緩，甚至逆轉”的長期目標。

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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