吡喹酮类似物在Cestode TRPMPZQ上的靶向设计

IF 3.8 2区医学 Q2 CHEMISTRY, MEDICINAL

ACS Infectious Diseases Pub Date : 2025-08-03 DOI:10.1021/acsinfecdis.5c00449

Daniel J Sprague, Sang-Kyu Park, Marc Kaethner, Claudia M Rohr, Mina R Ghobrial, D Connor Barth, David Maillard, Thomas Spangenberg, Britta Lundström-Stadelmann, Jonathan S Marchant

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引用次数: 0

摘要

吡喹酮（PZQ）用于治疗由寄生扁虫引起的临床和兽医感染已有几十年的历史。虽然PZQ对许多不同类型的吸虫和绦虫有效，但对某些类型的寄生虫，包括假茶树绦虫，PZQ的活性较低。PZQ的靶点是寄生扁虫瞬时受体电位离子通道（TRPMPZQ），对该靶点的研究为理解PZQ在不同寄生虫之间的疗效差异以及基于靶点的设计策略如何帮助提供新的类似物，提高对目前难以治疗的疾病的疗效提供了机会。在本研究中，我们考虑了cestode TRPMPZQ结合口袋中天然氨基酸的变化，设计了对假茶碱类cestode TRPMPZQ更有效的PZQ硫酰胺衍生物。基于靶标的寄生虫TRPMPZQ同源物设计，以及该离子通道家族中的其他TRPM同源物，为扩展和改进当前的驱虫工具箱提供了机会。

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Target-Based Design of Praziquantel Analogs at Cestode TRPM_PZQ.

The drug praziquantel (PZQ) has been used for decades to treat clinical and veterinary infections caused by parasitic flatworms. Although PZQ is efficacious against many different types of flukes and tapeworms, PZQ activity is lower against certain types of parasites, including pseudophyllidean cestodes. The target of PZQ is a parasitic flatworm transient receptor potential ion channel (TRPM_PZQ), and interrogation of this target affords the opportunity to understand why PZQ efficacy varies between different parasites and how target-based design strategies could help deliver new analogs with improved efficacy against currently hard-to-treat diseases. In this study, we consider natural amino acid variation within cestode TRPM_PZQ binding pockets to design thioamide derivatives of PZQ with greater efficacy at pseudophyllidean cestode TRPM_PZQ. Target-based design across parasite TRPM_PZQ orthologues, as well as at other TRPM paralogues in this ion channel family, provides an opportunity to expand and improve on the current anthelmintic toolbox.

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来源期刊

ACS Infectious Diseases CHEMISTRY, MEDICINALINFECTIOUS DISEASES&nb-INFECTIOUS DISEASES

CiteScore

9.70

自引率

3.80%

发文量

213

期刊介绍： ACS Infectious Diseases will be the first journal to highlight chemistry and its role in this multidisciplinary and collaborative research area. The journal will cover a diverse array of topics including, but not limited to: * Discovery and development of new antimicrobial agents — identified through target- or phenotypic-based approaches as well as compounds that induce synergy with antimicrobials. * Characterization and validation of drug target or pathways — use of single target and genome-wide knockdown and knockouts, biochemical studies, structural biology, new technologies to facilitate characterization and prioritization of potential drug targets. * Mechanism of drug resistance — fundamental research that advances our understanding of resistance; strategies to prevent resistance. * Mechanisms of action — use of genetic, metabolomic, and activity- and affinity-based protein profiling to elucidate the mechanism of action of clinical and experimental antimicrobial agents. * Host-pathogen interactions — tools for studying host-pathogen interactions, cellular biochemistry of hosts and pathogens, and molecular interactions of pathogens with host microbiota. * Small molecule vaccine adjuvants for infectious disease. * Viral and bacterial biochemistry and molecular biology.