药学学报, 2022, 57(5): 1282-1288
引用本文:
柴常伟, 张翼翔, 张海婧*, 吴练秋*. 治疗炎症性肠道疾病的新兴靶点与药物[J]. 药学学报, 2022, 57(5): 1282-1288.
CHAI Chang-wei, ZHANG Yi-xiang, ZHANG Hai-jing*, WU Lian-qiu*. Emerging targets and drugs of inflammatory bowel disease[J]. Acta Pharmaceutica Sinica, 2022, 57(5): 1282-1288.

治疗炎症性肠道疾病的新兴靶点与药物
柴常伟, 张翼翔, 张海婧*, 吴练秋*
中国医学科学院、北京协和医学院药物研究所, 北京 100050
摘要:
炎症性肠道疾病(inflammatory bowel disease,IBD)是一种慢性的、反复的肠道炎症疾病。临床上常用的治疗药物在长期应用后都存在疗效不佳、不良反应多等缺点。新型生物疗法如抗肿瘤坏死因子单抗在克服常用药不良反应的同时,也存在价格昂贵、不易储存和应用后耐药和复发等问题。近年来,针对IBD新的治疗药物不断出现,如抑制淋巴细胞迁移的调节剂(整合素抑制剂和鞘氨醇-1磷脂受体激动剂)已进入IBD的临床治疗。还有炎性细胞因子抑制剂[白细胞介素23抑制剂、Janus激酶(Janus kinases,JAKs)抑制剂、磷酸二酯酶抑制剂等]、靶向纤维化和肠道组织降解和重塑的抑制剂(基质金属蛋白酶抑制剂)等也正在进行IBD的临床试验评估。本文以药物作用机制为切入点,总结和梳理了当前IBD治疗的主流药物和一些新兴药物的进展,并介绍其作用靶点,以期为IBD药物的设计和研发提供新的思路。
关键词:    炎症性肠道疾病      溃疡性结肠炎      克罗恩病      机制      靶点     
Emerging targets and drugs of inflammatory bowel disease
CHAI Chang-wei, ZHANG Yi-xiang, ZHANG Hai-jing*, WU Lian-qiu*
Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China
Abstract:
Inflammatory bowel disease (IBD) is a chronic, repeated intestinal inflammatory disease. Clinically commonly used therapeutic drugs have some disadvantages, such as poor efficacy and many adverse reactions after long-term application. Although new biological therapies such as anti-tumor necrosis factor agents, overcome common adverse reactions, also have problems such as high price, difficult storage, drug resistance and recurrence after application. In recent years, many new therapeutic methods for inflammatory bowel disease have emerged, for example, modulators that inhibit lymphocyte migration (integrin inhibitors and sphingosine 1-phosphate receptor agonists) have been introduced into the clinical treatment of inflammatory bowel disease, inflammatory cytokine inhibitors (interleukin-23 inhibitors, Janus kinase inhibitors, phosphodiesterase inhibitors, etc.) and inhibitors targeting fibrosis and intestinal tissue degradation and remodeling (matrix metalloproteinase inhibitors) are also being evaluated in clinical trials of IBD. Based on the mechanisms of action, this paper intends to outline the current mainstream IBD therapies and some emerging drugs, and briefly introduce their targets to provide reference for IBD drug design and development.
Key words:    inflammatory bowel disease    ulcerative colitis    Crohn's disease    mechanism    target   
收稿日期: 2021-11-01
DOI: 10.16438/j.0513-4870.2021-1563
基金项目: 中国医学科学院中央级公益性科研院所基本科研业务费(2020-JKCS-019).
通讯作者: 吴练秋,Tel:86-10-63031589,Fax:86-10-63035779,E-mail:wlq@imm.ac.cn;张海婧,E-mail:zhanghaijing@imm.ac.cn
Email: wlq@imm.ac.cn;zhanghaijing@imm.ac.cn
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参考文献:
[1] Park J, Cheon JH. Incidence and prevalence of inflammatory bowel disease across Asia[J]. Yonsei Med J, 2021, 62:99-108.
[2] Ananthakrishnan AN. Epidemiology and risk factors for IBD[J]. Nat Rev Gastroenterol Hepatol, 2015, 12:205-217.
[3] Colombel JF, Sandborn WJ, Reinisch W, et al. Infliximab, azathioprine, or combination therapy for Crohn's disease[J]. N Engl J Med, 2010, 362:1383-1395.
[4] Colombel JF, Rutgeerts PJ, Sandborn WJ, et al. Adalimumab induces deep remission in patients with Crohn's disease[J]. Clin Gastroenterol Hepatol, 2014, 12:414-422.e5.
[5] Sandborn WJ, Feagan BG, Rutgeerts P, et al. Vedolizumab as induction and maintenance therapy for Crohn's disease[J]. N Engl J Med, 2013, 369:711-721.
[6] Allgayer H. Review article:mechanisms of action of mesalazine in preventing colorectal carcinoma in inflammatory bowel disease[J]. Aliment Pharmacol Ther, 2003, 18 Suppl 2:10-14.
[7] Lim WC, Wang Y, MacDonald JK, et al. Aminosalicylates for induction of remission or response in Crohn's disease[J]. Cochrane Database Syst Rev, 2016, 7:CD008870.
[8] Atreya I, Diall A, Dvorsky R, et al. Designer thiopurine-analogues for optimised immunosuppression in inflammatory bowel diseases[J]. J Crohns Colitis, 2016, 10:1132-1143.
[9] D'Haens G, Geboes K, Ponette E, et al. Healing of severe recurrent ileitis with azathioprine therapy in patients with Crohn's disease[J]. Gastroenterology, 1997, 112:1475-1481.
[10] Oancea I, Movva R, Das I, et al. Colonic microbiota can promote rapid local improvement of murine colitis by thioguanine independently of T lymphocytes and host metabolism[J]. Gut, 2017, 66:59-69.
[11] Tiede I, Fritz G, Strand S, et al. CD28-dependent Rac1 activation is the molecular target of azathioprine in primary human CD4+ T lymphocytes[J]. J Clin Invest, 2003, 111:1133-1145.
[12] Feagan BG, Fedorak RN, Irvine EJ, et al. A comparison of methotrexate with placebo for the maintenance of remission in Crohn's disease. North American Crohn's Study Group Investigators[J]. N Engl J Med, 2000, 342:1627-1632.
[13] Feuerstein JD, Akbari M, Tapper EB, et al. Systematic review and meta-analysis of third-line salvage therapy with infliximab or cyclosporine in severe ulcerative colitis[J]. Ann Gastroenterol, 2016, 29:341-347.
[14] Podolsky DK, Lobb R, King N, et al. Attenuation of colitis in the cotton-top tamarin by anti-alpha 4 integrin monoclonal antibody[J]. J Clin Invest, 1993, 92:372-380.
[15] Picarella D, Hurlbut P, Rottman J, et al. Monoclonal antibodies specific for beta 7 integrin and mucosal addressin cell adhesion molecule-1(MAdCAM-1) reduce inflammation in the colon of scid mice reconstituted with CD45RBhigh CD4+ T cells[J]. J Immunol, 1997, 158:2099-2106.
[16] Ghosh S, Goldin E, Gordon FH, et al. Natalizumab for active Crohn's disease[J]. N Engl J Med, 2003, 348:24-32.
[17] Sandborn WJ, Colombel JF, Enns R, et al. Natalizumab induction and maintenance therapy for Crohn's disease[J]. N Engl J Med, 2005, 353:1912-1925.
[18] Targan SR, Feagan BG, Fedorak RN, et al. Natalizumab for the treatment of active Crohn's disease:results of the ENCORE trial[J]. Gastroenterology, 2007, 132:1672-1683.
[19] Van Assche G, Van Ranst M, Sciot R, et al. Progressive multi-focal leukoencephalopathy after natalizumab therapy for Crohn's disease[J]. N Engl J Med, 2005, 353:362-368.
[20] Al-Bawardy B, Shivashankar R, Proctor DD. Novel and emerging therapies for inflammatory bowel disease[J]. Front Pharmacol, 2021, 12:651415.
[21] Sandborn WJ, Vermeire S, Tyrrell H, et al. Etrolizumab for the treatment of ulcerative colitis and Crohn's disease:an overview of the phase 3 clinical program[J]. Adv Ther, 2020, 37:3417-3431.
[22] Vermeire S, O'Byrne S, Keir M, et al. Etrolizumab as induction therapy for ulcerative colitis:a randomised, controlled, phase 2 trial[J]. Lancet, 2014, 384:309-318.
[23] Gonzalez-Cabrera PJ, Brown S, Studer SM, et al. S1P signaling:new therapies and opportunities[J]. F1000Prime Rep, 2014, 6:109.
[24] Snider AJ, Kawamori T, Bradshaw SG, et al. A role for sphingosine kinase 1 in dextran sulfate sodium-induced colitis[J]. FASEB J, 2009, 23:143-152.
[25] Deguchi Y, Andoh A, Yagi Y, et al. The S1P receptor modulator FTY720 prevents the development of experimental colitis in mice[J]. Oncol Rep, 2006, 16:699-703.
[26] Degagné E, Saba JD. S1pping fire:sphingosine-1-phosphate signaling as an emerging target in inflammatory bowel disease and colitis-associated cancer[J]. Clin Exp Gastroenterol, 2014, 7:205-214.
[27] Cohen JA, Arnold DL, Comi G, et al. Safety and efficacy of the selective sphingosine 1-phosphate receptor modulator ozanimod in relapsing multiple sclerosis (RADIANCE):a randomised, placebo-controlled, phase 2 trial[J]. Lancet Neurol, 2016, 15:373-381.
[28] Cohen JA, Comi G, Selmaj KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (RADIANCE):a multicentre, randomised, 24-month, phase 3 trial[J]. Lancet Neurol, 2019, 18:1021-1033.
[29] Comi G, Kappos L, Selmaj KW, et al. Safety and efficacy of ozanimod versus interferon beta-1a in relapsing multiple sclerosis (SUNBEAM):a multicentre, randomised, minimum 12-month, phase 3 trial[J]. Lancet Neurol, 2019, 18:1009-1020.
[30] Sandborn WJ, Peyrin-Biroulet L, Zhang J, et al. Efficacy and safety of etrasimod in a phase 2 randomized trial of patients with ulcerative colitis[J]. Gastroenterology, 2020, 158:550-561.
[31] Perez-Jeldres T, Alvarez-Lobos M, Rivera-Nieves J. Targeting sphingosine-1-phosphate signaling in immune-mediated diseases:beyond multiple sclerosis[J]. Drugs, 2021, 81:985-1002.
[32] Popp V, Gerlach K, Mott S, et al. Rectal delivery of a DNAzyme that specifically blocks the transcription factor GATA3 and reduces colitis in mice[J]. Gastroenterology, 2017, 152:176-192.e5.
[33] Withers DR, Hepworth MR, Wang X, et al. Transient inhibition of ROR-γt therapeutically limits intestinal inflammation by reducing TH17 cells and preserving group 3 innate lymphoid cells[J]. Nat Med, 2016, 22:319-323.
[34] Fuss IJ, Becker C, Yang Z, et al. Both IL-12p70 and IL-23 are synthesized during active Crohn's disease and are down-regu-lated by treatment with anti-IL-12 p40 monoclonal antibody[J]. Inflamm Bowel Dis, 2006, 12:9-15.
[35] Feagan BG, Sandborn WJ, D'Haens G, et al. Induction therapy with the selective interleukin-23 inhibitor risankizumab in patients with moderate-to-severe Crohn's disease:a randomised, double-blind, placebo-controlled phase 2 study[J]. Lancet, 2017, 389:1699-1709.
[36] Feagan BG, Sandborn WJ, Gasink C, et al. Ustekinumab as induction and maintenance therapy for Crohn's disease[J]. N Engl J Med, 2016, 375:1946-1960.
[37] Sands BE, Sandborn WJ, Panaccione R, et al. Ustekinumab as induction and maintenance therapy for ulcerative colitis[J]. N Engl J Med, 2019, 381:1201-1214.
[38] Sandborn WJ, Ferrante M, Bhandari BR, et al. Efficacy and safety of mirikizumab in a randomized phase 2 study of patients with ulcerative colitis[J]. Gastroenterology, 2020, 158:537-549.e10.
[39] Boland BS, Sandborn WJ, Chang JT. Update on Janus kinase antagonists in inflammatory bowel disease[J]. Gastroenterol Clin North Am, 2014, 43:603-617.
[40] Gerlach K, Hwang Y, Nikolaev A, et al. TH9 cells that express the transcription factor PU.1 drive T cell-mediated colitis via IL-9 receptor signaling in intestinal epithelial cells[J]. Nat Immunol, 2014, 15:676-686.
[41] Monteleone G, Monteleone I, Fina D, et al. Interleukin-21 enhances T-helper cell type I signaling and interferon-gamma production in Crohn's disease[J]. Gastroenterology, 2005, 128:687-694.
[42] Shinohara T, Nemoto Y, Kanai T, et al. Upregulated IL-7 receptor α expression on colitogenic memory CD4+ T cells may parti-cipate in the development and persistence of chronic colitis[J]. J Immunol, 2011, 186:2623-2632.
[43] Sandborn WJ, Su C, Panes J. Tofacitinib as induction and main-tenance therapy for ulcerative colitis[J]. N Engl J Med, 2017, 377:496-497.
[44] Mazur M, Karczewski J, Lodyga M, et al. Inhibitors of phosphodiesterase 4(PDE 4):a new therapeutic option in the treatment of psoriasis vulgaris and psoriatic arthritis[J]. J Dermatolog Treat, 2014, 26:326-328.
[45] Nighot P, Al-Sadi R, Rawat M, et al. Matrix metalloproteinase 9-induced increase in intestinal epithelial tight junction permeability contributes to the severity of experimental DSS colitis[J]. Am J Physiol Gastrointest Liver Physiol, 2015, 309:G988-G997.
[46] Matusiewicz M, Neubauer K, Mierzchala-Pasierb M, et al. Matrix metalloproteinase-9:its interplay with angiogenic factors in inflammatory bowel diseases[J]. Dis Markers, 2014, 2014:643645.
[47] Marshall DC, Lyman SK, McCauley S, et al. Selective allosteric inhibition of MMP9 is efficacious in preclinical models of ulcerative colitis and colorectal cancer[J]. PLoS One, 2015, 10:e0127063.
[48] Sandborn WJ, Bhandari BR, Randall C, et al. Andecaliximab[anti-matrix Metalloproteinase-9] induction therapy for ulcerative colitis:a randomised, double-blind, placebo-controlled, phase 2/3 study in patients with moderate to severe disease[J]. J Crohns Colitis, 2018, 12:1021-1029.
[49] Suzuki K, Yokoyama J, Kawauchi Y, et al. Phase 1 clinical study of siRNA targeting carbohydrate sulphotransferase 15 in Crohn's disease patients with active mucosal lesions[J]. J Crohns Colitis, 2017, 11:221-228.
[50] Yan X, Liu Z, Chen Y. Regulation of TGF-beta signaling by Smad7[J]. Acta Biochim Biophys Sin, 2009, 41:263-272.
[51] Briones-Orta MA, Tecalco-Cruz AC, Sosa-Garrocho M, et al. Inhibitory Smad7:emerging roles in health and disease[J]. Curr Mol Pharmacol, 2011, 4:141-153.
[52] Monteleone G, Neurath MF, Ardizzone S, et al. Mongersen, an oral SMAD7 antisense oligonucleotide, and Crohn's disease[J]. N Engl J Med, 2015, 372:1104-1113.
[53] Monteleone G, Pallone F. Mongersen, an oral SMAD 7 antisense oligonucleotide, and Crohn's disease[J]. N Engl J Med, 2015, 372:2461.
[54] Lasaro MA, Salinger N, Zhang J, et al. F1C fimbriae play an important role in biofilm formation and intestinal colonization by the Escherichia coli commensal strain Nissle 1917[J]. Appl Environ Microbiol, 2009, 75:246-251.
[55] Scaldaferri F, Gerardi V, Mangiola F, et al. Role and mechanisms of action of Escherichia coli Nissle 1917 in the maintenance of remission in ulcerative colitis patients:an update[J]. World J Gastroenterol, 2016, 22:5505-5511.
[56] Rossen NG, Fuentes S, van der Spek MJ, et al. Findings from a randomized controlled trial of fecal transplantation for patients with ulcerative colitis[J]. Gastroenterology, 2015, 149:110-118.e4.
[57] Neurath MF, Travis SP. Mucosal healing in inflammatory bowel diseases:a systematic review[J]. Gut, 2012, 61:1619-1635.
[58] Bryant RV, Burger DC, Delo J, et al. Beyond endoscopic mucosal healing in UC:histological remission better predicts cortico-steroid use and hospitalisation over 6 years of follow-up[J]. Gut, 2016, 65:408-414.
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