The William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London, Charterhouse Square, EC1M 6BQ London, UK; Centre for Inflammation and Therapeutic Innovation, Queen Mary University of London, UK.
SynAct Pharma AB, Lund, Sweden.
Semin Immunol. 2022 Jan;59:101603. doi: 10.1016/j.smim.2022.101603. Epub 2022 Mar 25.
Melanocortin receptors have emerged as important targets with a very unusual versatility, as their widespread distribution on multiple tissues (e.g. skin, adrenal glands, brain, immune cells, exocrine glands) together with the variety of physiological processes they control (pigmentation, cortisol release, satiety mechanism, inflammation, secretions), place this family of receptors as genuine therapeutic targets for many disorders. This review focuses in the journey of the development of melanocortin receptors as therapeutic targets from the discovery of their existence in the early 1990 s to the approval of the first few drugs of this class. Two major areas of development characterise the current state of melanocortin drug development: their role in obesity, recently culminated with the approval of setmelanotide, and their potential for the treatment of chronic inflammatory and autoimmune diseases like rheumatoid arthritis, multiple sclerosis or fibrosis. The pro-resolving nature of these drugs offers the advantage of acting by mimicking the way our body naturally resolves inflammation, expecting fewer side effects and a more balanced (i.e. non-immunosuppressive) response from them. Here we also review the approaches followed for the design and development of novel compounds, the importance of the GPCR nature of these receptors in the process of drug development, therapeutic value, current challenges and successes, and the potential for the implementation of precision medicine approaches through the incorporation of genetics advances.
黑皮质素受体作为重要的靶点，具有非常独特的多功能性，因为它们广泛分布于多种组织（如皮肤、肾上腺、大脑、免疫细胞、外分泌腺），同时控制着多种生理过程（色素沉着、皮质醇释放、饱腹感机制、炎症、分泌），这使得该受体家族成为许多疾病的真正治疗靶点。这篇综述聚焦于黑皮质素受体作为治疗靶点的发展历程，从 20 世纪 90 年代初发现其存在到第一批此类药物获得批准。黑皮质素药物开发的当前状态有两个主要特点：它们在肥胖症中的作用，最近随着 setmelanotide 的批准达到顶峰，以及它们在治疗慢性炎症和自身免疫性疾病（如类风湿关节炎、多发性硬化症或纤维化）方面的潜力。这些药物的促解决特性具有通过模拟我们身体自然解决炎症的方式发挥作用的优势，预计副作用更少，反应更平衡（即非免疫抑制性）。在这里，我们还回顾了设计和开发新型化合物的方法，这些受体的 GPCR 性质在药物开发过程中的重要性，治疗价值，当前的挑战和成功，以及通过纳入遗传进展实施精准医学方法的潜力。
