Development of Novel Melanocortin-4 Receptor Peptide Agonists for the Treatment ofMC4R Haploinsufficiency

黑素皮质素多肽治疗集黑素(ImcireeTM)对治疗罕见的 肥胖综合征、POMC和瘦素受体缺陷。然而，这种药物对大多数人来说都是无效的 常见的综合征性肥胖，黑素皮质素-4受体(MC4R)缺乏(MC4R单倍体不足)，发现于 患病率超过1/1000人。此外，该药物在治疗饮食肥胖方面无效。在……里面 除了Imciree没有解决综合征患者未得到满足的医疗需求这一事实 由于MC4R缺乏而导致的肥胖，Imciree是四种黑素皮质素受体的泛激动剂及其原因 通过激活真皮和毛囊黑素细胞上的黑素皮质素-1受体(MC1R)而引起的色素沉着。 最后，Imciree的配方不理想，需要每天皮下给药。在我们的第一阶段 应用，我们建议开发黑素皮质素-3受体拮抗剂作为MC4R的多肽治疗药物 缺乏，因为MC3R是MC4R神经元的负调节因子。然而，在这个过程中， 开发目前仍在进行的这些分子，我们有了一个惊人的发现。基于 在第一阶段开始了广泛的结构-活性关系(SAR)工作，我们还确定了四个新的 MC4R激动剂家族。经验证的人类肥胖小鼠模型中选择的多肽的特征 MC4R缺乏症(MC4R+/-小鼠)，我们发现了两个家族的这些MC4R激动肽，不同于 免疫，对MC4R单倍体不足和饮食肥胖有显著的减肥效果。 最近的工作提供了这些多肽的修改版本，这些多肽也降低了MC1R的疗效。 最后，我们证明了黑素皮质素多肽可以通过以下方式在可注射的PLGA微球中形成 一种新的远程加载技术，可在30多天内稳定释放多肽，提供 有可能优化治疗窗口，提高患者依从性，并降低成本。在这 第二阶段应用，我们建议1)完成MC4R激动肽的化学开发，用于 MC4R缺乏症的治疗，2)针对多达三种多肽开发的完整的GLP前安全性研究 MC4R缺乏症的候选对象，以及3)制定和表征药物动力学、疗效和 这些多肽在人类MC4R缺乏症小鼠模型中的副作用概况。它的产物是 第二阶段STTR提案将成为MC4R治疗的一个或多个候选治疗方案 单倍性不足，以及这些疗法商业化的途径。

The melanocortin peptide therapeutic setmelanotide, (ImcivreeTM), is highly effective in the treatment of the rare obesity syndromes, POMC and leptin receptor deficiency. However, the drug is ineffective for the most common syndromic obesity, melanocortin-4 receptor (MC4R) deficiency (MC4R haploinsufficiency), found at a prevalence greater than 1/1000 individuals. Further, the drug is ineffective in the treatment of dietary obesity. In addition to the fact that Imcivree does not address the unmet medical needs in patients with syndromic obesity due to MC4R deficiency, Imcivree is a pan-agonist of four melanocortin receptors and causes hyperpigmentation by activating the melanocortin-1 receptor (MC1R) on dermal and follicular melanocytes. Lastly, the formulation of Imcivree is not ideal, requiring daily subcutaneous administration. In our Phase I application, we proposed to develop melanocortin-3 receptor antagonists as peptide therapeutics for MC4R deficiency, since the MC3R is a negative regulator of MC4R neurons. However, in the course of developing these molecules, currently still in progress, we made a striking discovery. Based on the extensive structure-activity relationship (SAR) work initiated in Phase 1, we also identified four novel families of MC4R agonists. Characterizing select peptides in a validated obese mouse model of human MC4R deficiency (MC4R+/- mice), we discovered two families of these MC4R agonist peptides that, unlike Imcivree, have significant weight loss efficacy in MC4R haploinsufficiency, as well as in dietary obesity. More recent work provides modified versions of these peptides that have reduced MC1R efficacy as well. Finally, we have shown that melanocortin peptides can be formulated in injectable PLGA microspheres by a new remote-loading technique, yielding steady release of peptide for more than 30 days offering the potential for optimizing the therapeutic window, improving patient compliance, and reducing cost. In this phase II application, we propose to 1) complete the chemical development of MC4R agonist peptides for the treatment of MC4R deficiency, 2) complete pre-GLP safety studies for up to three peptide development candidates for MC4R deficiency, and 3) formulate and characterize the pharmacokinetics, efficacy, and side effect profile of these peptides in our mouse model of human MC4R deficiency. The product of this Phase II STTR proposal will be one or more therapeutic candidates for the treatment of MC4R haploinsufficiency, and a pathway to commercialization of these therapeutics.