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

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。

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.