Harnessing the synergy between Conformetrix technology and crystallography to expedite identification of novel, selective a4b7 integrin inhibitors for the treatment of IBD

这个项目的目标是提供一种口服小分子抗炎药，用于治疗轻、重度炎症性肠病(IBD)。IBD是一组由宿主肠道菌群免疫反应失调引起的特发性疾病。最常见的亚型是溃疡性结肠炎(一种贯穿整个结肠的持续炎症带)和克罗恩病(穿壁性“跳跃性病变”，影响胃肠道的任何部分)。IBD患者分为轻、中、重三类。目前对轻度患者的标准治疗是氨基水杨酸盐，随着疾病严重程度的增加，逐渐发展为皮质类固醇，然后是免疫抑制剂。对轻中度患者的治疗反应喜忧参半，并与显著的副作用相关。对免疫抑制剂无效的中/重度患者将继续接受生物疗法，这将彻底改变中/重度疾病的治疗方法。不幸的是，相当大比例的患者对生物疗法没有反应，这往往是由于产生中和抗体。胃肠病学家已经明确了开发非生物制剂的明显需要，以有效地维持中/重度患者的缓解。这一需求也延伸到轻中度患者，在这些患者中，具有成本效益的口服、非生物、抗炎治疗具有更高的有效性和副作用，可以防止疾病的进展。C4X Discovery将使用其专有的Conformetrix技术，通过阐明它们在溶液中的3D形状，从已知配体中快速识别新的化学支架(S)。这项技术将与蛋白质结晶学协同使用，比较自由和结合配体的3D形状，以精确定位需要优化的分子的确切区域，从而识别出有效的抗炎化合物。一种有效、安全、口服的IBD小分子疗法可以满足IBD患者严重程度的医疗需求，并有助于减轻该病造成的重大经济负担。目前，英国有超过30万名IBD患者，而且患病率还在上升。2006年全国卫生系统对IBD的经济成本为7.2亿GB。一种有效的口服消炎剂将减少患者的住院次数，与生物制剂相比，商品成本更低，而且不需要去医院进行治疗，从而减少医疗保健负担，从而增加患者获得改变生活的疗法的机会。在患者和社区层面上的积极影响将是一种无痛、方便、谨慎的药物，减少社会污名。“

"The objective for this project is to deliver an oral, small molecule anti-inflammatory agent for the treatment of mild-severe, inflammatory bowel disease (IBD). IBD is a collection of idiopathic diseases caused by a dysregulated immune response to host intestinal microflora. The most common sub-types are ulcerative colitis (a continuous band of inflammation throughout the colon) and Crohn's disease (transmural, ""skip lesions"" affecting any segment of the gastrointestinal tract). IBD patients are stratified as mild, moderate or severe. The current standard treatment for mild patients is aminosalicylate progressing to corticosteroids and then immunosuppressants as disease severity increases. Treatment for mild-moderate patients sees mixed response and is associated with significant side-effects. Moderate/severe patients that do not respond to immunosuppressants are progressed on to biological therapies which have revolutionised the treatment of moderate/severe disease. Unfortunately, a significant proportion of patients do not respond to biological therapies often due to the production of neutralising antibodies. Gastroenterologists have identified a clear need to develop non-biological agents that effectively maintain remission in moderate/severe patients. This need also extends to mild-moderate patients where cost effective, oral, non-biological, anti-inflammatory treatments with improved efficacy and side effects could prevent disease progression.C4X Discovery will use its proprietary Conformetrix technology which has been previously been used to rapidly identify novel chemical scaffolds from known ligands, by elucidating their 3D shape(s) in solution. The technology will be used synergistically with protein crystallography to compare free and bound ligand 3D-shapes to pin-point the exact areas of the molecules that will need optimising leading to the identification of potent anti-inflammatory compounds.An effective, safe, oral small molecule therapy for IBD could meet the healthcare need across IBD patient severities and help reduce the significant economic burden caused by the disease. There are currently over 300,000 patients in the UK with IBD and prevalence increasing. The NHS economic cost of IBD was £720 million in 2006\. An effective oral anti-inflammatory agent will lower the healthcare burden by reduced hospitalisation of patients, lower Cost of Goods compared to biologics, and no necessity for hospital visits for administration, thereby increasing patient access to a life-changing therapy. The positive impact at a patient and community level would be a pain free, convenient, discreet medication reducing social stigma."