A PSGL-1 Glycopeptide Mimetic for Treatment of Metabolic Syndrome

 描述(申请人提供)：聚集的研究团队最近开发了新的合成方法，导致了一种新的PSGL-1糖肽模拟物GSnP-6的鉴定，它是PSGL-1/P-选择素相互作用的低纳摩尔拮抗剂。具体地说，GSnP-6被鉴定为旨在合理设计PSGL-1模拟物的筛选程序的结果，在该模拟物中保留了关键的、高亲和力的碳水化合物和肽识别表位。作为一种合成分子，GSnP-6易于进一步修饰，这为药物设计和给药提供了极大的灵活性。与这些努力相一致，最近的计算模拟已经证实，GSnP-6为设计一系列高效的选择素特异性拮抗剂提供了一个独特的结构支架，用于预防和治疗肥胖诱导的代谢综合征和胰岛素抵抗。利用GSnP-6作为药理“工具化合物”，我们打算：(1)确定GSnP-6在肥胖相关的胰岛素抵抗小鼠模型中的效力。在我们研究的第一阶段，我们将确定GSnP-6的药代动力学特征，以及GSnP-6的聚乙二醇偶联物。提供最佳给药方案的给药方案将被选择用于后续的体内研究。在这些研究的第二阶段，将使用饮食诱导肥胖的小鼠模型来确定GSnP-6和/或PEG-GSnP-6的疗效。这些研究将确定GSnP-6改善胰岛素敏感性和葡萄糖稳态的能力，以及减少肥胖引起的脂肪组织炎症变化的能力，从而验证这种治疗方法。(2)设计新的结构更简单、具有高选择素结合亲和力的PSGL-1糖链模拟物。分子动力学(MD)模拟表明，并不是所有天然PSGL-1配体或GSnP-6中的单糖都直接与结合亲和力有关。因此，将进行计算研究来指导结构-活性关系(SAR)研究并确定新的结构更简单的结构， 高亲和力的选择素抑制剂。目前，GSnP-6和相关的糖模拟物的合成采用化学-酶方案。然而，用于产生PSGL-1糖仿制的全化学合成的设计提供了提高总产率的潜在优势，并将作为这一目标的平行重点。(3)检测GSnP-6及其类似物对改善脂代谢、预防或逆转肝脏脂肪变性、抑制脂肪组织诱导的动脉粥样硬化的作用。肥胖会导致脂肪代谢受损、肝脏脂肪变性和动脉粥样硬化。在这些研究的第一阶段，将在喂养西方饮食的载脂蛋白E−/−小鼠身上评估GSnP-6和AIM 2中确定的最有希望的结构简化的P-选择素拮抗剂改善脂质代谢和预防肝脏脂肪变性的能力。在这些研究的第二阶段，我们将检验这些药物通过减轻全身促炎作用以及脂肪组织引发的血管周围炎症来限制载脂蛋白E−/−小鼠动脉粥样硬化的能力。

 DESCRIPTION (provided by applicant): The assembled investigative team has recently developed new synthetic approaches that have led to the identification of a novel PSGL-1 glycopeptide mimetic, GSnP-6, as a low nanomolar antagonist of PSGL- 1/P-selectin interactions. Specifically, GSnP-6 was identified as the result of a screening program directed at the rational design of PSGL-1 mimetics in which critical, high affinity, carbohydrate and peptide recognition epitopes were preserved. As a synthetic molecule, GSnP-6 is amenable to further modification, which provides for great flexibility in drug design and delivery. In concert with thee efforts, recent computational simulations have confirmed that GSnP-6 provides a unique structural scaffold for the design of a range of highly potent selectin-specific antagonists for prevention and treatment of obesity induced metabolic syndrome and insulin resistance. Using GSnP-6 as a pharmacological `tool compound', we intend to: (1) Define the potency of GSnP-6 in murine models of obesity associated insulin resistance. In the first phase of our investigations, we will define the pharmacokinetic profile of GSnP-6, as well as poly(ethylene glycol) (PEG) conjugates of GSnP-6. The dosing regimen that affords the best drug delivery profile will be selected for subsequent in vivo studies. In the second phase of these investigations, the efficacy of GSnP-6 and/or PEG-GSnP-6 will be defined using murine models of diet-induced obesity. These studies will define the capacity of GSnP-6 to improve insulin sensitivity and glucose homeostasis, as well as reduce obesity-induced inflammatory changes in adipose tissue, thus, validating this therapeutic approach. (2) Design new structurally simpler PSGL-1 glycomimetics that display high selectin binding affinity. Molecular dynamics (MD) simulations have indicated that not all of the monosaccharides in the native PSGL-1 ligand or GSnP-6 contribute directly to binding affinity. Thus, computational studies will be pursued to guide the structure-activity relationship (SAR) studies and to identify novel structurally simpler, high affinity selectin inhibitors. A chemo-enzymatic scheme is currently used for the synthesis of GSnP-6 and related glycomimetics. However, the design of a total chemical synthesis for the generation of PSGL-1 glycomimetics offers the potential advantage of improved overall yield and will serve as a parallel focus for this Aim. (3) Determine the effectiveness of GSnP-6 and related analogues to improve lipid metabolism, prevent or reverse hepatic steatosis, and limit adipose tissue induced atherosclerosis. Obesity leads to impaired lipid metabolism, hepatic steatosis, and atherosclerosis. In the first phase of these investigations, the ability of GSnP-6 and the most promising structurally simplified P-selectin antagonist identified in Aim 2 to improve lipid metabolism and prevent hepatic steatosis will be assessed in ApoE−/− mice fed a Western diet. In the second phase of these studies, we will examine the capacity of these agents to limit atherosclerosis in ApoE−/− mice by attenuating systemic pro-inflammatory effects, as well as adipose tissue induced perivascular inflammation.