Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana
Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana.
J Pharmacol Exp Ther. 2022 Sep;382(3):287-298. doi: 10.1124/jpet.122.001151. Epub 2022 Jun 10.
Urocortin-1 (UCN1) is a member of the corticotropin releasing hormone (CRH) family of peptides that acts through CRH-receptor 1 (CRHR1) and CRH-receptor 2 (CRHR2). UCN1 can induce the adrenocorticotropin hormone and downstream glucocorticoids through CRHR1 and promote beneficial metabolic effects through CRHR2. UCN1 has a short half-life and has been shown to improve experimental autoimmune disease. A pegylated UCN1 peptide (PEG-hUCN1) was generated to extend half-life and was tested in multiple experimental autoimmune disease models and in healthy mice to determine effects on corticosterone induction, autoimmune disease, and glucocorticoid induced adverse effects. Cardiovascular effects were also assessed by telemetry. PEG-hUCN1 demonstrated a dose dependent 4-6-fold elevation of serum corticosterone and significantly improved autoimmune disease comparable to prednisolone in several experimental models. In healthy mice, PEG-hUCN1 showed less adverse effects compared with corticosterone treatment. PEG-hUCN1 peptide induced an initial 30% reduction in blood pressure that was followed by a gradual and sustained 30% increase in blood pressure at the highest dose. Additionally, an adeno-associated viral 8 (AAV8) UCN1 was used to assess adverse effects of chronic elevation of UCN1 in wild type and CRHR2 knockout mice. Chronic UCN1 expression by an AAV8 approach in wild type and CRHR2 knockout mice demonstrated an important role of CRHR2 in countering the adverse metabolic effects of elevated corticosterone from UCN1. Our findings demonstrate that PEG-hUCN1 shows profound effects in treating autoimmune disease with an improved safety profile relative to corticosterone and that CRHR2 activity is important in metabolic regulation. SIGNIFICANCE STATEMENT: This study reports the generation and characterization of a pegylated UCN1 peptide and the role of CRHR2 in UCN1-induced metabolic effects. The potency/selectivity, pharmacokinetic properties, pharmacodynamic effects, and efficacy in four autoimmune models and safety profiles are presented. This pegylated UCN1 shows potential for treating autoimmune diseases with reduced adverse effects compared to corticosterone treatment. Continuous exposure to UCN1 through an AAV8 approach demonstrates some glucocorticoid mediated adverse metabolic effects that are exacerbated in the absence of the CRHR2 receptor.
尿皮质素-1（UCN1）是促肾上腺皮质激素释放激素（CRH）家族肽的成员，通过 CRH 受体 1（CRHR1）和 CRH 受体 2（CRHR2）发挥作用。UCN1 可以通过 CRHR1 诱导促肾上腺皮质激素激素和下游糖皮质激素，并通过 CRHR2 促进有益的代谢效应。UCN1 的半衰期较短，已被证明可改善实验性自身免疫性疾病。生成了一种聚乙二醇化的 UCN1 肽（PEG-hUCN1）以延长半衰期，并在多种实验性自身免疫性疾病模型和健康小鼠中进行了测试，以确定其对皮质酮诱导、自身免疫性疾病和糖皮质激素诱导的不良反应的影响。还通过遥测术评估了心血管效应。PEG-hUCN1 显示出剂量依赖性的血清皮质酮升高 4-6 倍，与几种实验模型中的泼尼松龙相比，显著改善了自身免疫性疾病。在健康小鼠中，与皮质酮治疗相比，PEG-hUCN1 显示出较少的不良反应。PEG-hUCN1 肽诱导初始血压降低 30%，随后在最高剂量下血压逐渐持续升高 30%。此外，使用腺相关病毒 8（AAV8）UCN1 评估野生型和 CRHR2 敲除小鼠中 UCN1 慢性升高的不良反应。野生型和 CRHR2 敲除小鼠中 AAV8 方法的慢性 UCN1 表达表明，CRHR2 在对抗 UCN1 升高的皮质酮的不良代谢作用方面具有重要作用。我们的研究结果表明，与皮质酮相比，PEG-hUCN1 在治疗自身免疫性疾病方面具有显著效果，且具有改善的安全性，并且 CRHR2 活性在代谢调节中很重要。意义声明：本研究报告了一种聚乙二醇化 UCN1 肽的生成和特征，以及 CRHR2 在 UCN1 诱导的代谢效应中的作用。介绍了其效力/选择性、药代动力学特性、药效学效应以及在四种自身免疫模型中的疗效和安全性概况。与皮质酮治疗相比，这种聚乙二醇化 UCN1 具有治疗自身免疫性疾病的潜力，且不良反应减少。通过 AAV8 方法持续暴露于 UCN1 会导致一些糖皮质激素介导的不良代谢效应，而在缺乏 CRHR2 受体的情况下，这些效应会加剧。
