Institute for Research in Biomedicine (IRB-Barcelona), The Barcelona Institute of Science and Technology, Barcelona, Spain.
Departament de Ciències Experimentals i de la Salut, Universitat Pompeu Fabra, Barcelona, Spain.
Nat Commun. 2021 Mar 25;12(1):1869. doi: 10.1038/s41467-021-22076-5.
Ulcerative colitis and Crohn's disease are forms of inflammatory bowel disease whose incidence and prevalence are increasing worldwide. These diseases lead to chronic inflammation of the gastrointestinal tract as a result of an abnormal response of the immune system. Recent studies positioned Cortistatin, which shows low stability in plasma, as a candidate for IBD treatment. Here, using NMR structural information, we design five Cortistatin analogues adopting selected native Cortistatin conformations in solution. One of them, A5, preserves the anti-inflammatory and immunomodulatory activities of Cortistatin in vitro and in mouse models of the disease. Additionally, A5 displays an increased half-life in serum and a unique receptor binding profile, thereby overcoming the limitations of the native Cortistatin as a therapeutic agent. This study provides an efficient approach to the rational design of Cortistatin analogues and opens up new possibilities for the treatment of patients that fail to respond to other therapies.
溃疡性结肠炎和克罗恩病是炎症性肠病的两种形式，其发病率和患病率在全球范围内呈上升趋势。这些疾病导致胃肠道的慢性炎症，是由于免疫系统的异常反应。最近的研究将皮质抑素（Cortistatin）定位为 IBD 治疗的候选药物，但其在血浆中的稳定性较低。在这里，我们使用 NMR 结构信息，根据溶液中选择的天然皮质抑素构象设计了五种皮质抑素类似物。其中一种类似物 A5 保留了皮质抑素在体外和疾病小鼠模型中的抗炎和免疫调节活性。此外，A5 在血清中的半衰期延长，具有独特的受体结合谱，从而克服了天然皮质抑素作为治疗剂的局限性。本研究为皮质抑素类似物的合理设计提供了一种有效方法，为那些对其他治疗方法无反应的患者的治疗开辟了新的可能性。
