Department of Cell Biology, Neurobiology, and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA.
Program in Chemical Biology, Department of Biochemistry, Medical College of Wisconsin, Milwaukee, WI, USA.
Nat Struct Mol Biol. 2024 Sep;31(9):1386-1393. doi: 10.1038/s41594-024-01298-3. Epub 2024 May 7.
Diseases caused by parasitic flatworms impart a considerable healthcare burden worldwide. Many of these diseases-for example, the parasitic blood fluke infection schistosomiasis-are treated with the drug praziquantel (PZQ). However, PZQ is ineffective against disease caused by liver flukes from the genus Fasciola because of a single amino acid change within the target of PZQ, a transient receptor potential ion channel in the melastatin family (TRPM), in Fasciola species. Here, we identify benzamidoquinazolinone analogs that are active against Fasciola TRPM. Structure-activity studies define an optimized ligand (BZQ) that caused protracted paralysis and tegumental damage to these liver flukes. BZQ also retained activity against Schistosoma mansoni comparable to PZQ and was active against TRPM orthologs in all profiled species of parasitic fluke. This broad-spectrum activity manifests as BZQ adopts a pose within the binding pocket of TRPM that is dependent on a ubiquitously conserved residue. BZQ therefore acts as a universal activator of trematode TRPM and a first-in-class, broad-spectrum flukicide.
由寄生扁形动物引起的疾病在全球范围内给医疗保健带来了相当大的负担。许多此类疾病，例如寄生性血吸虫害血吸虫病，都采用药物吡喹酮（PZQ）进行治疗。然而，由于 PZQ 的靶标，即黑素小体家族（TRPM）中的瞬时受体电位离子通道中的一个单一氨基酸变化，PZQ 对来自片形属的肝吸虫引起的疾病无效。在这里，我们鉴定了对 Fasciola TRPM 具有活性的苯甲酰胺喹唑啉酮类似物。构效关系研究确定了一种优化的配体（BZQ），它可导致这些肝吸虫长时间瘫痪和表皮损伤。BZQ 对曼氏血吸虫也保持与 PZQ 相当的活性，并且对所有鉴定的寄生吸虫物种的 TRPM 同源物均具有活性。这种广谱活性表现为 BZQ 在 TRPM 的结合口袋内采用一种构象，该构象依赖于普遍保守的残基。因此，BZQ 作为一种通用的吸虫 TRPM 激活剂和一类新型的广谱杀吸虫剂。
