Department of Radiation Oncology, Stanford University, Palo Alto, California, USA.
Palo Alto Veterans Institute for Research, Veterans Affairs Palo Alto Health Care System, Palo Alto, California, USA.
Sci Rep. 2019 May 9;9(1):7178. doi: 10.1038/s41598-019-43428-8.
Small molecules that disrupt leukocyte trafficking have proven effective in treating patients with multiple sclerosis (MS). We previously reported that chemerin receptor chemokine-like receptor 1 (CMKLR1) is required for maximal clinical and histological experimental autoimmune encephalomyelitis (EAE); and identified CMKLR1 small molecule antagonist 2-(α-naphthoyl) ethyltrimethylammonium iodide (α-NETA) that significantly suppressed disease onset in vivo. Here we directly compared α-NETA versus FDA-approved MS drug Tecfidera for clinical efficacy in EAE; characterized key safety/toxicity parameters for α-NETA; identified structure-activity relationships among α-NETA domains and CMKLR1 inhibition; and evaluated improved α-NETA analogs for in vivo efficacy. α-NETA proved safe and superior to Tecfidera in suppressing clinical EAE. In addition, we discovered structurally differentiated α-NETA analogs (primarily ortho- or para-methoxy substitutions) with significantly improved target potency in vitro and improved efficacy in vivo. These findings suggest that α-NETA-based CMKLR1 inhibitors may prove safe and effective in treating demyelinating diseases and potentially other autoimmune disorders.
小分子白细胞迁移抑制剂已被证明可有效治疗多发性硬化症（MS）患者。我们之前曾报道过 Chemerin 受体趋化因子样受体 1（CMKLR1）对于最大程度的实验性自身免疫性脑脊髓炎（EAE）的临床和组织学表现是必需的；并确定了 CMKLR1 小分子拮抗剂 2-（α-萘酰基）乙基三甲基氯化铵（α-NETA），它可显著抑制体内疾病的发作。在这里，我们直接比较了 α-NETA 与 FDA 批准的 MS 药物 Tecfidera 在 EAE 中的临床疗效；对 α-NETA 的关键安全性/毒性参数进行了特征描述；确定了 α-NETA 结构域与 CMKLR1 抑制之间的构效关系；并评估了体内功效的改进型 α-NETA 类似物。α-NETA 在抑制临床 EAE 方面既安全又优于 Tecfidera。此外，我们发现了结构上不同的 α-NETA 类似物（主要是邻位或对位甲氧基取代），它们在体外对靶标的效力显著提高，体内疗效也得到改善。这些发现表明，基于 α-NETA 的 CMKLR1 抑制剂可能在治疗脱髓鞘疾病和潜在的其他自身免疫性疾病方面既安全又有效。
