Structure-based strategy for developing inhibitors of the kidney chloride channel CLC-Ka

基于结构的策略开发肾氯通道抑制剂 CLC-Ka

• 批准号: 10491286
• 负责人: Merritt C Maduke
• 金额: $ 64.47万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-20 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491286
• 关键词: Anions; BCL2L11 gene; Binding; Biological Assay; Bone Diseases; CLC Gene; Cattle; Cerebrum; Cessation of life; Chloride Channels; Chlorides; Cirrhosis; Clinical; Coma; Complex; Cryoelectron Microscopy; Data; Development; Disease; Docking; Drug Kinetics; Drug Targeting; Electrophysiology (science); Epithelial Cells; Excretory function; FDA approved; Family; Formulation; Goals; Headache; Heart failure; Homologous Gene; Human; Hydration status; Hypertension; Hyponatremia; In Vitro; Ion Channel; Kidney; Kidney Diseases; Lead; Lethargies; Ligands; Limb structure; Location; Malaise; Membrane Proteins; Metabolism; Modification; Molecular; Molecular Structure; Mus; Myopathy; Nephrons; Neurologic; Oral; Organism; Output; Pathologic; Patients; Pharmaceutical Chemistry; Pharmacology; Physiological; Play; Positioning Attribute; Potassium Channel; Process; Property; Proteins; Receptor Inhibition; Research; Resolution; Risk; Role; Safety; Site-Directed Mutagenesis; Sodium Chloride; Structure; Testing; Thick; Thinness; Toxic effect; Urine; Vasopressins; Water; Work; base; benzimidazole; design; drug candidate; drug development; drug discovery; drug metabolism; falls; improved; in vivo; in vivo evaluation; inhibitor; insight; kidney interstitial tissue; liver injury; microscopic imaging; mutant; nervous system disorder; next generation; novel; public health relevance; receptor; scaffold; screening; solute; success; tolvaptan; tool

CLCs (the “Chloride Channel” family) are anion-selective transporters and channels ubiquitous in all organisms. Among them, CLC-Ka and CLC-Kb are essential for Cl– and water handling in the kidney. CLC-Ka is localized to the thin ascending limb, where it helps to establish the steep solute gradient in the inner medullary interstitium that drives renal water reabsorption. As such, CLC-Ka is a potential drug target for treating pathologic water retention (hyponatremia) that frequently complicates the management of patients with hypertension, heart failure, or cirrhosis. A specific CLC-Ka inhibitor would be invaluable for validating CLC-Ka as a drug target for manipulating renal water excretion. In this project, we leverage recent breakthroughs to develop selective CLC-Ka inhibitors. The first breakthrough is our discovery of BIM1, a substituted benzimidazole that displays >20-fold selectivity for CLC-Ka over its closest homolog CLC-Kb. The synthetic accessibility of BIM derivatives makes them well suited for further development. The second breakthrough is the revolution in cryo-electron microscopy, which enables high-resolution structure determination of challenging targets, including ion channels. A molecular structure of the BIM/CLC-K complex will identify which regions of the BIM molecule must be retained for potency/selectivity and which may be modified to improve pharmacokinetic properties. Guided by this information, we will use a medicinal chemistry approach to develop BIM derivatives with optimized potency, selectivity, and pharmacokinetic properties. Optimized BIM derivatives will be tested for in vivo efficacy.

CLC（“氯离子通道”家族）是阴离子选择性转运蛋白和通道，在细胞中普遍存在。 所有的有机体。其中，CLC-Ka和CLC-Kb是处理Cl-和水的必需物质， 肾CLC-Ka定位于薄的上升翼，在那里它有助于建立陡峭的溶质 驱动肾水重吸收的内髓髓质中的梯度。因此，CLC-Ka 是治疗病理性水潴留（低钠血症）的潜在药物靶点， 使高血压、心力衰竭或肝硬化患者的管理复杂化。特定 CLC-Ka抑制剂对于验证CLC-Ka作为操纵肾功能的药物靶点是非常宝贵的。 水排泄在这个项目中，我们利用最近的突破来开发选择性CLC-Ka 抑制剂的第一个突破是我们发现了BIM 1，一种取代的苯并咪唑， 对CLC-Ka的选择性超过其最接近的同系物CLC-Kb的20倍。合成 BIM衍生产品的可访问性使其非常适合进一步开发。第二 突破性进展是低温电子显微镜的革命，它可以实现高分辨率 挑战性目标的结构测定，包括离子通道。的分子结构 BIM/CLC-K复合物将识别BIM分子的哪些区域必须保留， 其可以被修饰以改善药代动力学性质。指导 根据这些信息，我们将使用药物化学方法开发BIM衍生物， 优化的效力、选择性和药代动力学性质。优化的BIM衍生产品将 测试体内功效。