Computationally informed discovery of scavenging-sparing inhibitors of CC chemokine receptor 2

通过计算发现 CC 趋化因子受体 2 的清除抑制剂

• 批准号: 10057631
• 负责人: Irina Kufareva
• 金额: $ 23.63万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-04 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10057631
• 关键词: Agonist; Atherosclerosis; Autoimmune Diseases; Back; Behavior; Binding; Biological Assay; Biology; CC chemokine receptor 2; CCL2 gene; Cell surface; Chemicals; Clinic; Clinical; Complement; Complex; Coupled; Coupling; Disease; Environment; Failure; Fibrosis; Future; GTP-Binding Proteins; Goals; Hand; Human; In Vitro; Inflammation; Inflammatory; Investigation; Leukocytes; Libraries; Malignant Neoplasms; Measures; Mediating; Modeling; Molecular Conformation; Multiple Sclerosis; Myocardial Infarction; Outcome; Pathogenesis; Patients; Pharmacology; Plasma; Process; Proteins; Receptor Inhibition; Recycling; Rheumatoid Arthritis; Role; Safety; Sampling; Series; Side; Signal Transduction; Structure; Testing; Therapeutic; Tissues; Work; base; cell motility; chemical binding; chemokine; chemokine receptor; clinical candidate; clinical efficacy; conformational conversion; conformer; coronary fibrosis; design; follow-up; in silico; in vivo; inhibitor/antagonist; insight; macrophage; migration; molecular dynamics; monocyte; novel; painful neuropathy; prevent; receptor; receptor binding; receptor internalization; recruit; response; screening; side effect; small molecule; targeted agent; therapeutic target; three-dimensional modeling; tool; tumor-immune system interactions; virtual screening

The G protein-coupled CC chemokine receptor 2 (CCR2) is expressed on circulating monocytes and drives their recruitment to infected and damaged tissues, where the monocytes differentiate into infiltrating macrophages and promote the formation of an inflammatory pro-fibrotic environment. Because this process is key to the pathogenesis of many inflammatory diseases (rheumatoid arthritis, multiple sclerosis, neuropathic pain, and fibrosis, among others), CCR2 has been pursued for decades as a therapeutic target. However, no anti-CCR2 therapeutics have so far made it to the clinic, with most failing for lack of efficacy. Paradoxically, all known CCR2 antagonists cause a profound elevation in plasma levels of CCR2 agonist chemokine CCL2, which they were designed to inhibit in the first place. The therapeutic consequences of this are not clear: the elevation may be a desired (via blunting of chemokine gradients and migratory responses) or an unwanted (via “inhibition of an inhibitor”) phenomenon. Additional complexity arises from non-migratory functions of CCL2 in e.g. regulating leukocyte differentiation. Concerningly, antagonist-induced CCL2 elevation reaches its peak when the plasma concentration of the antagonist itself wanes. Therefore, this side effect may compromise the safety and efficacy of anti-CCR2 clinical candidates. Unfortunately, systematic investigation of this phenomenon in vivo is currently impossible, for the lack of proper pharmacological tools. The applicants’ long-term goal is to decipher the intricacies of CCR2 signaling and to develop clinically successful CCR2-targeting agents. The applicants have recently discovered the basis for antagonist-induced CCL2 elevation, and demonstrated that it occurs via inhibition of an important but underappreciated regulatory function of CCR2 where it scavenges CCL2 constitutively produced by tissues, and clears it from plasma. Scavenging is inhibited because all known antagonists prevent chemokine binding to CCR2. These findings outline the conceptual possibility of an antagonist of CCR2-mediated migration that does not cause CCL2 elevation, by sparing chemokine binding to CCR2 and hence its scavenging. The goal of the present proposal is to discover such antagonists via a computationally guided approach, by pursuing two Specific Aims: (1) Via in silico compound library screening against an ensemble of CCR2:CCL2 complex models, identify chemicals that bind CCR2 concurrently with CCL2, and characterize their pharmacology in vitro. (2) Computationally elucidate the dynamics of CCR2 in complex with CCL2, and identify G-protein- incompatible states with the potential to enrich for scavenging-sparing inhibitors in VLS. The outcome of the proposed work will be the discovery of the first chemical probes with novel pharmacology in relation to CCR2: the inhibitors of CCR2-mediated cell migration that spare CCL2 scavenging. These molecules will assist investigations of antagonist-induced CCL2 elevation in vivo by the applicant’s group and others. The findings will also inform future efforts of therapeutic targeting of CCR2 for inflammation and cancer.

G蛋白偶联的CC趋化因子受体2（CCR 2）在循环单核细胞上表达，并驱动它们的分化。 募集到受感染和受损的组织，在那里单核细胞分化成浸润性巨噬细胞 并促进炎性促纤维化环境的形成。因为这个过程是 许多炎性疾病（类风湿性关节炎、多发性硬化、神经性疼痛和 纤维化等），CCR 2作为治疗靶标已经被追求了几十年。然而，没有抗CCR 2 迄今为止，治疗方法已经进入临床，但大多数都因缺乏疗效而失败。 巧合的是，所有已知的CCR 2拮抗剂引起CCR 2激动剂的血浆水平的显著升高 趋化因子CCL 2，它们被设计为首先抑制。这种治疗效果 尚不清楚：升高可能是期望的（通过趋化因子梯度和迁移反应的钝化）或 一种不想要的（通过“抑制剂的抑制”）现象。额外的复杂性来自于非迁移性 CCL 2在例如调节白细胞分化中的功能。令人担忧的是，拮抗剂诱导的CCL 2升高 当拮抗剂本身的血浆浓度降低时达到其峰值。因此，这种副作用可能 损害抗CCR 2临床候选药物的安全性和有效性。不幸的是，系统的调查 由于缺乏适当的药理学工具，这种现象在体内目前是不可能的。 申请人的长期目标是破译CCR 2信号传导的复杂性，并开发临床上成功的 CCR 2靶向剂。申请人最近发现了拮抗剂诱导的CCL 2的基础 升高，并证明它是通过抑制一个重要的，但低估的调节功能发生的 在那里它清除由组织组成性产生的CCL 2，并将其从血浆中清除。扫气 抑制，因为所有已知的拮抗剂阻止趋化因子与CCR 2结合。这些发现概述了 CCR 2介导的迁移拮抗剂的概念可能性，不引起CCL 2升高，通过 避免趋化因子与CCR 2结合并因此避免其清除。本提案的目标是发现 这种拮抗剂通过计算指导的方法，通过追求两个特定的目标：（1）通过计算机模拟 针对CCR 2：CCL 2复合物模型的集合进行化合物文库筛选， 同时结合CCR 2和CCL 2，并在体外表征其药理学。（二） 计算阐明CCR 2与CCL 2复合的动力学，并鉴定G蛋白- 不相容的状态，有可能在VLS中富集清除-节约抑制剂。 这项工作的成果将是发现第一个具有新药理学的化学探针， 与CCR 2的关系：CCR 2介导的细胞迁移抑制剂，可避免CCL 2清除。这些分子 将有助于申请人的小组和其他人在体内研究拮抗剂诱导的CCL 2升高。的 这些发现也将为未来针对炎症和癌症的CCR 2治疗提供信息。