Crofelemer

Crofelemer delayed-release tablets are Jaguar's FDA-approved prescription drug under botanical guidance ("botanical drug") derived from the Croton lechleri tree. Crofelemer, in a novel liquid formulation, is being developed as the potential first oral adjunctive therapy for Intestinal Failure (IF) from microvillus inclusion disease (MVID) and short bowel syndrome (SBS) Crofelemer development with novel formulations for different gastrointestinal disorders reflects a differentiated botanical drug platform integrating ethnobotanical medicine, sustainable harvesting, complex CMC, and novel bioassays to support approval under FDA botanical guidance Traditional knowledge of Croton lechleri use supported ethnobotanical research that led to development and approval of crofelemer, whose first in class anti-secretory mechanism was characterized through modern pharmacology and mechanism-based bioassays. Recent milestones include continued evaluation in an extension phase for Jaguar family company Napo's pivotal clinical trial of crofelemer as adjunctive therapy to Parenteral Support (PS) for MVID and upcoming ESPGHAN presentations in pediatric MVID and SBS-IF patients FDA approval of crofelemer as an oral botanical drug highlights the totality-of-evidence and creates a significant practical barrier to generic replication SAN FRANCISCO, CA / ACCESS Newswire / May 28, 2026 / Jaguar Health, Inc. (NASDAQ:JAGX) (Jaguar) and family company Napo Pharmaceuticals (Napo) today highlighted how the Company's long-standing research in ethnobotanical medicine, sustainable harvesting, and regulatory drug development under botanical guidance ("botanical drug") continues to inform the development of crofelemer as a novel oral adjunctive therapy to PS for rare congenital gastrointestinal intestinal failure (IF) disorders, including microvillus inclusion disease (MVID) and short bowel syndrome (SBS). It has been through direct research collaboration with indigenous experts on plant and ethnobotanical medicine that Napo team members learned about the use of extracts of Croton lechleri to treat a number of gastrointestinal conditions. We have had cross-cultural medical discussions with traditional healers - a methodology that provides an opportunity to elucidate new ways of treating unmet medical needs such as IF. Napo has been collaborating on the long term sustainable harvest of Croton lechleri in the Central and Northern Peruvian Amazon for several decades, and this is being done with 19 distinct indigenous cultural groups in more than 30 locations. Crofelemer is a refined and highly characterized botanical drug substance consisting of a complex oligomeric proanthocyanidin mixture derived from the latex of the Croton lechleri tree. Crofelemer is distinct from the raw traditional preparation and is the first and only oral botanical drug approved by the FDA. It was developed and approved as a delayed-release tablet through botanical identification, controlled sustainable harvesting, chemical characterization, biological testing, and clinical development. "We are proud to be collaborating and interdependent with the people and tropical forest ecosystems of Peru . The world continues to learn that the conservation of tropical forests is often most effectively assured by the indigenous peoples who have been sustainably managing these ecosystems for centuries. They are dependent upon the water, air, animals, and plants of the forests for their physical and spiritual well-being, as is the rest of the world. They honor their relationship with the nurturing elements of their tropical forest homes. It is clear that the cultural and ecological health of people and forests are intertwined at multiple levels, and we wish to express our gratitude to these people and communities who have been working with and teaching members of our team for several decades how to sustainably manage this valuable medicinal plant within their ecosystems. They continue to integrate the Dragon's Blood tree, as Croton lechleri is referred to locally, into numerous creative reforestation strategies, as part of their sophisticated agroforestry and medicinal plant production systems," Dr. King added. "Crofelemer represents a differentiated pharmaceutical development story: traditional medicinal knowledge helped identify a promising botanical source, and modern drug development transformed that knowledge into a highly characterized FDA-approved prescription drug under botanical guidance," said Lisa Conte , Jaguar's Founder, President, and CEO. "We believe Jaguar's experience with crofelemer - including sustainable harvesting, botanical CMC, mechanism-based bioassays, clinical development, and regulatory engagement, is directly relevant as we advance crofelemer for rare intestinal failure disorders such as microvillus inclusion disease and short bowel syndrome with intestinal failure. We also believe the specialized know-how required to develop and manufacture crofelemer represents a distinct competency for Jaguar." Jaguar's family company, Napo Pharmaceuticals , is developing a novel crofelemer powder for oral solution for rare and orphan gastrointestinal disorders involving intestinal failure, including MVID and SBS-IF. This investigational formulation is distinct from Mytesi®, the FDA-approved delayed-release tablet formulation of crofelemer indicated for symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy. MVID is an ultrarare congenital enteropathy with life-threatening dehydration beginning in infancy. Patients with MVID require life-sustaining and lifelong PS, including total parenteral nutrition (TPN) and supplemental intravenous fluids, to maintain hydration, electrolyte balance, nutrition, and support growth. In addition to MVID pathology, TPN is associated with significant co-morbidities. SBS-IF is a serious condition in which patients are unable to absorb sufficient fluids and nutrients through the intestine and also require life-sustaining PS for daily nutritional, electrolyte, and fluid requirements. Recent clinical, scientific, and regulatory milestones in crofelemer intestinal failure development Jaguar has recently announced multiple milestones supporting the Company's crofelemer development strategy for intestinal failure: Clinical trial extension phase in MVID: Jaguar continues its pivotal trial in MVID with an extension phase for oral liquid crofelemer. The company has also announced active-treatment-only continuation of its pivotal multicenter clinical trial in pediatric patients with MVID to support a potential New Drug Application (NDA) for crofelemer powder for oral solution targeted for mid-2027. Clinical trial extension phase in MVID: Jaguar continues its pivotal trial in MVID with an extension phase for oral liquid crofelemer. The company has also announced active-treatment-only continuation of its pivotal multicenter clinical trial in pediatric patients with MVID to support a potential New Drug Application (NDA) for crofelemer powder for oral solution targeted for mid-2027. ESPGHAN late-breaking abstracts: Jaguar announced acceptance of two late-breaking abstracts for liquid oral crofelemer treatment of intestinal failure in pediatric patients at the 58th Annual Meeting of the European Society for Pediatric Gastroenterology , Hepatology & Nutrition (ESPGHAN). These include presentations related to pediatric intestinal failure patients receiving liquid oral crofelemer as an investigational drug under separate investigator-initiated and expanded access studies. ESPGHAN late-breaking abstracts: Jaguar announced acceptance of two late-breaking abstracts for liquid oral crofelemer treatment of intestinal failure in pediatric patients at the 58th Annual Meeting of the European Society for Pediatric Gastroenterology , Hepatology & Nutrition (ESPGHAN). These include presentations related to pediatric intestinal failure patients receiving liquid oral crofelemer as an investigational drug under separate investigator-initiated and expanded access studies. Prior proof-of-concept results presented at NASPGHAN 2025: Jaguar previously announced initial proof-of-concept results showing that a liquid formulation of crofelemer reduced required TPN and/or supplementary intravenous fluids, collectively referred to as parenteral support (PS), in patients with intestinal failure due to MVID and SBS-IF of up to 37% in the first participating MVID patient and up to 15% in participating SBS-IF patients Prior proof-of-concept results presented at NASPGHAN 2025: Jaguar previously announced initial proof-of-concept results showing that a liquid formulation of crofelemer reduced required TPN and/or supplementary intravenous fluids, collectively referred to as parenteral support (PS), in patients with intestinal failure due to MVID and SBS-IF of up to 37% in the first participating MVID patient and up to 15% in participating SBS-IF patients Botanical drug CMC publication: A recent review article by Luo and Wu, "CMC Challenges and Solutions in Botanical IND & NDA Development - Lessons Learned from Four Approved Botanical Drugs," published in Botanical Drugs, discusses Mytesi/crofelemer as a key FDA-approved botanical drug case study. The article highlights the CMC and quality-control challenges associated with botanical drugs and describes how crofelemer required eco-geographic raw material controls, mechanism-relevant chloride-channel bioassays, and multi-batch clinical consistency evidence to support FDA approval. Crofelemer CMC complexity represents a potent barrier to generic or competitive replication. Botanical drug CMC publication: A recent review article by Luo and Wu, "CMC Challenges and Solutions in Botanical IND & NDA Development - Lessons Learned from Four Approved Botanical Drugs," published in Botanical Drugs, discusses Mytesi/crofelemer as a key FDA-approved botanical drug case study. The article highlights the CMC and quality-control challenges associated with botanical drugs and describes how crofelemer required eco-geographic raw material controls, mechanism-relevant chloride-channel bioassays, and multi-batch clinical consistency evidence to support FDA approval. Crofelemer CMC complexity represents a potent barrier to generic or competitive replication. "Crofelemer's complexity is not simply a scientific challenge - it is also a strategic differentiator. The modern development of crofelemer illustrates why botanical drug development requires specialized expertise," said Steven King , PhD, Jaguar's Chief Sustainable Supply, Ethnobotanical Research , and Intellectual Property Officer. "Traditional medicinal use of Croton lechleri provided an important ethnobotanical starting point, yet crofelemer is a refined and highly characterized extract derived from Croton lechleri latex. Its development required research on sustainable harvesting, collaboration with multiple indigenous communities, conservation, pharmacology, quality control, manufacturing, and clinical research. This is the kind of long-term translational work that can connect traditional medicinal knowledge to modern drug development in a responsible and scientifically rigorous way." Crofelemer's first-in-class anti-secretory mechanism of action involves inhibitory modulation of intestinal chloride ion secretion through effects on two chloride ion channels in the intestinal membrane, including the cystic fibrosis transmembrane conductance regulator (CFTR) and calcium-activated chloride channels. This novel anti-secretory mechanism may be relevant to reducing the need for PS in rare intestinal failure disorders through reductions of excessive intestinal fluid loss and reduced needs for parenteral support. "Biopharma investors and business development partners often focus on synthetic small molecules, biologics, gene therapies, and other familiar innovation categories," Conte added. "Crofelemer demonstrates another model of innovation: a botanical drug discovered through ethnobotanical research, developed through rigorous pharmaceutical standards, approved by FDA in one indication, and now being evaluated in genetically defined rare GI disorders with substantial unmet medical need. We believe this combination of scientific differentiation, regulatory precedent, CMC complexity, and rare disease development creates a compelling opportunity for patients in need and all Jaguar stakeholders." About Crofelemer Crofelemer is Jaguar's novel, oral, plant-based prescription drug derived from the latex of the Croton lechleri tree. Crofelemer is approved in tablet formulation by the U.S. FDA under the brand name Mytesi® for the symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy. Crofelemer is a first-in-class anti-secretory agent acting locally in the gastrointestinal tract. Jaguar family companies, Napo Pharmaceuticals, Inc. , and Napo Therapeutics s.P.A. are developing crofelemer for multiple potential follow-on indications, with a novel powder for oral solution for rare intestinal failure (IF) disorders such as microvillus inclusion disease (MVID) and short bowel syndrome with intestinal failure (SBS-IF), as well as other indications involving intestinal fluid loss. About Mytesi®Mytesi® (crofelemer delayed-release tablets) is an antidiarrheal indicated for the symptomatic relief of noninfectious diarrhea in adult patients with HIV/AIDS on antiretroviral therapy (ART). Mytesi is not indicated for the treatment of infectious diarrhea. Rule out infectious etiologies of diarrhea before starting Mytesi. If infectious etiologies are not considered, there is a risk that patients with infectious etiologies will not receive the appropriate therapy and their disease may worsen. In clinical studies, the most common adverse reactions occurring at a rate greater than placebo were upper respiratory tract infection (5.7%), bronchitis (3.9%), cough (3.5%), flatulence (3.1%), and increased bilirubin (3.1%). See full Prescribing Information at Mytesi.com. About Jaguar Health , Napo Pharmaceuticals , and Napo Therapeutics s.P.A. Jaguar Health, Inc. is a commercial-stage pharmaceutical company focused on developing novel, plant-based, sustainably derived prescription medicines for people and animals with gastrointestinal distress, including chronic, debilitating disorders. Jaguar's family companies, Napo Pharmaceuticals and Napo Therapeutics, focus on developing and commercializing proprietary human prescription pharmaceuticals for rare diseases from plants used traditionally in rainforest areas. For more information about Jaguar Health , please visit https://jaguar.health. Forward-Looking Statements Certain statements in this press release constitute "forward-looking statements." These include statements regarding Jaguar's expectation that crofelemer may be developed for microvillus inclusion disease (MVID) and short bowel syndrome with intestinal failure (SBS-IF); Jaguar's belief that crofelemer's mechanism of action may be relevant to serious rare disorders characterized by excessive intestinal fluid loss; Jaguar's expectations regarding the potential therapeutic utility of crofelemer in rare gastrointestinal disorders; Jaguar's plans to pursue development pathways for crofelemer in microvillus inclusion disease (MVID) and short bowel syndrome with intestinal failure (SBS-IF); and Jaguar's belief that its ethnobotanical research, sustainable sourcing expertise, botanical CMC capabilities, and FDA botanical drug development experience represent differentiating capabilities. In some cases, forward-looking statements can be identified by terms such as "believe," "may," "will," "expects," "plans," "anticipates," "intends," "potential," "continue," "designed," or similar expressions. These statements involve substantial risks and uncertainties, including risks related to Jaguar's ability to successfully develop crofelemer for microvillus inclusion disease (MVID), short bowel syndrome with intestinal failure (SBS-IF), or other potential indications; the risk that clinical studies may not demonstrate safety or efficacy; the risk that regulatory authorities may not agree with Jaguar's proposed development or approval pathways; the risk that Jaguar may not be able to obtain or maintain regulatory approvals; the risk that Jaguar may not be able to secure sufficient financing, partnerships, or other resources to advance its development programs; and other risks described in Jaguar's filings with the Securities and Exchange Commission. Forward-looking statements speak only as of the date they are made. Jaguar undertakes no obligation to update any forward-looking statements, except as required by applicable law. Contact: hello@jaguar.healthJaguar-JAGX SOURCE: Jaguar Health, Inc.

源于天然的多靶标组合药物研发思考与实践 曾昊   杨华**   李 萍** 中国药科大学 多靶标天然药物全国重点实验室 作者简介 杨   华     中国药科大学二级教授，中药学院院长、多靶标天然药物全国重点实验室常务副主任。主要从事数据驱动的中药药效物质与创新药物研发，主持国家自然科学基金项目、国家重点研发计划项目等，获中国青年科技奖、教育部科技进步奖一等奖等荣誉。 李   萍     中国药科大学二级教授，多靶标天然药物全国重点实验室主任。主要从事中药活性成分群发现与作用机理研究，主持国家自然科学基金创新研究群体项目、重点项目等，获国家科技进步奖二等奖等荣誉。 曾   昊     中国药科大学副研究员。主要从事心血管疾病的代谢冗余调控机制及中药多靶标协同干预研究，主持国家自然科学基金面上项目、青年科学基金项目（C类）等，获国际中医药与传统医药高影响力成果奖。 摘  要 天然药物承载着人类几千年的临床实践经验，是应对重大健康挑战的关键战略资源之一。以中药复方为代表的天然来源药物，凭借多成分、多靶标、多环节调控优势，在慢性复杂性疾病的防治中展现出独特价值，蕴藏着构建慢病治疗新体系的巨大潜力。立足我国丰富的天然药物资源，系统构建具有自身特色的研究理论技术体系，对于我国未来生物医药发展具有重要战略意义。为此，本文聚焦源于天然的多靶标组合药物研发，探讨了其主要特征、作用基础、整合作用、研发路径等，旨在依托我国天然药物资源与中医药优势构建自主创新体系，为新药研发模式的转变和创新提供思路和借鉴。 关键词：天然药物；中药复方；多靶标组合药物；重大慢病   天然药物通常是指来源于植物、动物、微生物、海洋生物、矿物等天然来源的药物，其中植物药是主体，人体或细菌内源活性物质也属于此范畴。纵观全球医学史，从我国中医药到古印度、古希腊等传统医学体系，均积累了系统应用天然药物的宝贵经验。天然药物的整体性及系统性调控特点，与慢性疾病复杂的网络化作用特征高度契合，使得其在防治慢性复杂性疾病方面独具优势[1，2]。随着现代科技的发展，国际上天然药物研究逐渐形成两种主流路径：一是聚焦强活性物质发现，催生了青霉素、紫杉醇、阿司匹林、青蒿素等药物；二是关注整体系统调控，着眼于多成分、多靶标的协同整合作用，以遵循“君臣佐使”原则配伍的中药复方为典型代表。 随着多组学、人工智能等技术的快速发展，天然药物中“何种成分作用于何种靶标，以及各成分间、靶标间如何协同整合”等核心科学问题正在被逐步解析。在此基础上，针对恶性肿瘤、心脑血管、代谢性疾病等慢性复杂性疾病多环节多靶标干预特征，系统挖掘确有疗效天然药物与中药复方的作用特点与规律，构建源于天然的多靶标组合药物（以下简称“多靶标天然药物”）研发理论与方法，将为新药研发模式的转变与创新提供关键支撑。 1   多靶标天然药物的主要特征 源于天然的多靶标组合药物是指针对特定疾病防治的、直接或间接来源于天然的、具有协同增效或减毒作用的组合药物。主要包括：（1）精制中药提取物、中药有效部位组合、组分中药，如桑枝总生物碱片、银杏二萜内酯葡胺注射液、注射用丹参多酚酸盐等[3-5]；（2）特定天然成分及比例的组合药物，如从复方丹参制剂中发现的代表抗心肌缺血作用的18种成分的组合（中药等效成分群）[6，7]；（3）天然产物衍生物的组合药物，如青蒿素组合药物[8，9]；（4）以天然协同组分发现协同作用靶标（组合靶标），进而设计获得的组合药物，可为一药多靶或多药多靶，如熊去氧胆小檗碱[10]。 总而言之，多靶标天然药物是以天然来源（植物、动物、微生物及其复方）为起点，经靶标或表型筛选、优化重组，最终得到的化学组成清晰、作用机理明确、质量稳定可控的组合型药物。其核心作用模式并非经典的“锁—钥”式单一靶点结合，而是通过多组分协同干预疾病网络，经多靶标协同作用，实现对疾病的系统调控。 2   多靶标天然药物的作用基础 2.1  临床实践 天然药物伴随人类社会存在而存在，18世纪以前一直是人类疾病的主要治疗药物。数千年的临床实践，为天然药物的疾病防治积累了极其丰富的经验；近年循证医学研究也确证了一些中药治疗慢性复杂性疾病的临床疗效和安全性，如芪苈强心胶囊治疗心衰[11，12]等。同时，国际上对天然药物的研究也愈加重视，美国食品药品监督管理局（Food and Drug Administration，FDA）2006年首次批准植物药绿茶提取物Veregen，2012年批准首例口服植物药Fulyzaq，2016年发布新版《植物药研发指南》[13]；欧盟2022年批准全球首款大疱性表皮松解症伤口治疗药物桦树皮提取物Filsuvez[14]。 传统医学体系思想，尤其是我国中医药理论，更是为多靶标天然药物研发提供了指导方向。中医药整体观认为疾病源于机体整体功能失衡，主张多环节联动调节，为复杂疾病的整合干预提供了原创思路；辨证论治则强调根据证候、病机及个体状态动态调整治疗方案，形成针对不同疾病阶段和病理状态进行组合干预的实践积累；性味归经、升降浮沉等理论从药物属性、作用部位和趋向角度归纳药效特点，为组合筛选、作用特征分析和功能方向判断提供参考；君臣佐使及配伍法则强调药物间的协同、互补与制约关系，积累了关于配伍规律、剂量及安全性平衡的用药经验。这些理论与实践经验互为支撑，共同构成了多靶标组合药物研发的理论基础。 2.2  化学基础 天然药物的化学成分具有结构多样性、新颖性以及功能独特性，一直是创新药物研发的重要来源，目前使用的各类药物中约45%源自天然产物[15]。其涵盖多糖、核苷酸、氨基酸等初生代谢产物，以及生物碱、黄酮、萜类、酚酸类等次生代谢产物。天然产物结构多样性来源于生物体在应对环境胁迫、种间竞争和病原侵袭等过程中形成的化学适应策略[16-18]。与合成药物相比，这些功能性代谢产物通常具有更独特的化学骨架、更丰富的功能基团和更复杂的立体构型。在长期自然选择过程中，为适应复杂环境，天然药物中多种化学成分之间也逐渐形成了协同、缓冲或互补的组合特征，体现出复杂生物系统的稳健性与适应性。 现代研究表明，天然药物的化学结构多样性，是其多靶标整合调节作用的物质基础。体系中的不同成分，可同时或序贯作用于慢性复杂性疾病网络中的多个节点，通过协同、叠加或拮抗等效应，实现对病理过程的系统调控。相比于单一成分的高选择性干预，这种多组分体系更易维持生物网络的动态平衡，减少耐药性产生，并拓宽治疗的安全窗口。从系统生物学或网络药理学的视角看，天然药物的化学组合可被视为一种经过亿万年进化优化的“天然药效网络”，为多靶标天然药物研究提供了化学基础。 2.3  生物学基础 现代药理学与系统生物学研究，正从微观到宏观层面逐步揭示天然药物多靶标、多层次的作用机制，为其系统调控优势提供了科学依据。现代研究表明，低剂量天然成分可作为温和的刺激物，激活细胞的内源性防御体系以增强对病理过程的抵抗能力[19]；部分天然产物及天然来源代谢物可通过影响内源性代谢环境、受体配体系统及其下游信号网络，参与器官间串扰与稳态调节，从而产生接近生理调节的干预效应[20-22]；免疫双向调节机制通过对免疫细胞多受体及信号通路的协同作用，能够根据机体免疫状态调整应答方向，进而重建免疫稳态[23]；代谢重编程的调控路径则能通过调控关键代谢酶和转录因子，重塑细胞能量与物质代谢，从而纠正系统的代谢紊乱[24，25]。 以上这些机制的探索推动了对于天然药物系统调控作用的科学认识：天然组合中的多种活性成分以强、中、低亲和力协同作用于疾病网络的多个环节，通过累积效应与网络效应显著增强整体疗效，同时提升生物系统自身的稳健性与自我修复能力。该作用模式不仅与慢性病的多因性、动态性特点相契合，也为从系统层面理解药物—机体复杂互作提供了新的思路。 3   多靶标天然药物的整合作用 多靶标天然药物对于疾病的协同调控作用，依赖于其多种化学成分对疾病网络的多层次整合干预。主要包括三个维度：一是对疾病网络的直接干预，二是对机体内环境稳态的间接重塑，三是多成分在体内过程中的代谢协同。 3.1  直接干预 天然活性成分通过与疾病可干预的关键节点（如受体、酶、转录因子等）直接结合，进而发挥药效作用。例如，百合地黄汤中的毛蕊花糖苷与阿魏酸可分别与核因子—红细胞-2—相关因子2（Nuclear factor-erythroid 2 Related Factor 2，NRF2）的不同氨基酸残基形成氢键，协同稳定其蛋白构象，从而改善小鼠神经炎症[26]。又如，复方黄黛片中的四硫化四砷、丹参酮ⅡA与靛玉红可分别靶向降解促癌蛋白PML-RARα、促进白血病细胞分化以及抑制其增殖，协同抑制急性早幼粒细胞白血病进展[27]。 3.2  间接调控 天然活性成分可通过调节内源代谢、细胞间通讯和跨器官/跨物种互作等间接方式恢复机体内环境稳态。例如，葛根素结合迷走神经背侧核（Dorsal Motor nucleus of the Vagus，DMV）的γ‌-氨基丁酸（Gamma-Aminobutyric Acid，GABA）受体抑制空肠神经元，缩短微绒毛减少脂肪吸收，通过“脑—肠轴”减重[28]。又如，源于黄连—黄芩药对的活性成分小檗碱与汉黄芩素以3∶1比例联用，可通过调节HIF1α/HIF2α通路发挥协同降脂作用，从而显著改善肥胖相关胰岛素抵抗[29]。再如，在新冠肺炎的治疗中，化湿败毒方同时抑制SARS-CoV-2复制和宿主磷酸二酯酶4（Phosphodiesterase 4，PDE4）介导的炎症，实现抗病毒—抗炎双重调控[30]。 3.3  体内代谢协同 天然活性成分可通过影响彼此在生物体内的吸收、分布、代谢（生物转化）和排泄过程，实现协同增强疗效或降低毒性。例如，附子与甘草配伍时，甘草中的甘草酸、甘草黄酮等成分可抑制肠道外排转运体P-糖蛋白（P-glycoprotein，P-gp）、乳腺癌耐药蛋白（Breast Cancer Resistance Protein，BCRP）和多药耐药相关蛋白2（Multidrug Resistance-associated Protein 2，MRP2），减少乌头碱类有毒成分的吸收，同时提高有效成分的生物利用度，从而减轻附子毒性[31]。又如，大黄与黄芩配伍时，大黄酸通过抑制肠道和肝脏中BCRP介导的黄芩苷外排，提高黄芩苷的血药浓度，增强其清热解毒效果并减少不良反应[32]。 4   多靶标天然药物的研发路径 4.1  基于传统医学理论与表型筛选技术的多靶标天然药物研发 该路径核心在于从传统医学理论（如中医药理论）、真实临床获益和用药规律出发，挖掘天然药物（如中药复方）特色临床表型，建立与之相适配的模型和评价体系。首先，根据真实世界临床数据、医保用药结构、医院信息系统及文献资料，结合自然语言处理、知识图谱、机器学习等方法，系统挖掘中药复方的临床应用规律及其优势特征，重点识别现有化学药或生物药疗效不足、副作用明显或尚缺乏有效干预手段的临床表型，明确潜在的临床获益点。进一步根据临床挖掘获得的表型特征（如特定证候群、疾病亚型或治疗抵抗状态），构建能够模拟相应表型的体内外模型，包括基因工程动物模型、原代细胞共培养体系、类器官、器官芯片等，使其尽可能再现关键临床特征及治疗响应模式，为药物筛选提供具有临床相关性的评价平台。基于上述建立的模型，利用中药等效成分群筛选、方证代谢组学等技术，从天然药物（中药复方）中快速识别能够显著改善疾病表型的等效或优效成分组合，明确其药效特点和量效关系，围绕适应症、目标人群和治疗阶段明确临床定位，从而推动候选药物进入后续转化开发。这一路径旨在将中药复方整体调节、辨证论治等临床优势转化为可验证、可追踪、可复制的多靶标药物研发模式，服务于未被满足的临床需求。 4.2  基于天然成分/组分库与组合筛选的多靶标天然药物研发 该路径核心在于构建大规模天然成分/组分库，通过疾病相关靶标或表型筛选，明确成分/组分作用特征，进而针对疾病网络的多个关键节点或环节进行系统化的组合筛选与优化。首先，系统制备来源于植物、动物、微生物、海洋生物等天然资源的化学成分或组分（包括小分子、多肽、多糖、核酸等），建立标准化、高覆盖度的实体库及信息数据库。其次，聚焦疾病相关的代谢紊乱、纤维化、微循环障碍等关键病理环节及可干预的分子节点，建立多维表型/靶标筛选模型，明确不同化学成分/组分的药效作用。在此基础上，根据其成分作用特点或者不同病理环节，设置不同成分组合干预方案（如不同给药时序、剂量及配比等），比较不同干预方式的作用效果，获得候选组合药物。这一路径充分发挥了天然成分化学结构多样性与多成分组合网络调控的独特优势，突破了传统“单靶点—单成分”药物研发范式，为复杂慢性疾病的多靶标治疗提供新的解决方案。 4.3  基于协同靶标组与优化设计的多靶标天然药物研发 该路径核心在于以天然协同成分为基础，解析各成分的分子靶标，进而发现并确证协同靶标组，据此开展新型组合药物的理性设计与优化。首先，围绕天然协同成分组合，根据其结构特点运用亲和捕获、化学蛋白质组学等技术，发现并确证各成分的直接作用靶标，确证成分—靶标互作及其与药效表型的关联。其次，针对已确证的活性成分靶标，结合生物信息学分析、化学干预或基因干预等手段，解析其上下游级联调控关系，扩展可干预的关键节点，确定优效协同靶标组。进一步以协同成分组合的天然骨架或关键药效团为基础开展组合药物的理性设计与优化。这一路径通过系统解析天然药物协同效应的生物学基础，为基于靶标组或靶标网络的药物组合设计提供科学依据，具有重要的应用前景和价值（图1）。 5   总结与展望 天然药物（中药复方）蕴含丰富的多成分、多靶标和多层级的病症调控信息，是现代组合药物研发的重要资源，但其研发仍面临一系列关键难点。（1）天然药物复杂体系中共存成分数量多、丰度差异大、相互作用关系非线性，且药效作用常呈现明显的时序性与动态性，使得真正与疗效密切相关的关键成分群（尤其是低丰度成分）难以从大量背景成分中准确识别。（2）复杂体系中化学特征与药效表型之间往往缺乏直接对应关系，而且天然活性成分往往具有弱亲和、多靶标和间接调控等特征，其作用常涉及代谢调节、跨器官信号传递以及菌群—宿主互作等复杂过程，使得天然成分—靶标互作规律认知不足，尤其是弱亲和、多靶标和间接调控条件下的靶标发现与确证评价体系不完善。（3）天然成分整合作用机理涉及多成分、多靶点、多细胞类型及多器官互作的动态过程，具有时空依赖性和非线性特征，传统单一层次或静态研究方法难以同时捕捉其动态分布、异质性响应和系统效应，仍缺乏从分子事件解析到整体表型评价的研究范式。（4）组分中药、多成分组合药物等在注册分类、审评审批等方面还需进一步优化完善。 但也应看到，随着贴近临床表型的多层次评价模型、高通量高覆盖多组学技术（单细胞转录组、空间蛋白质组、代谢组等）以及人工智能算法（深度学习、知识图谱、因果推断模型）等的应用，上述难点正在逐步获得突破，有望为AI与数据驱动的多靶标天然药物研发提供系统解决方案。 参考文献（略） 关于《中国科学基金》 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