Abstract
Given the worldwide burden of neglected tropical diseases, there is ongoing need to develop novel anthelmintic agents to strengthen the pipeline of drugs to combat these burdensome infections. Many diseases caused by parasitic flatworms are treated using the anthelmintic drug praziquantel (PZQ), employed for decades as the key clinical agent to treat schistosomiasis. PZQ activates a flatworm transient receptor potential (TRP) channel within the melastatin family (TRPMPZQ) to mediate sustained Ca2+ influx and worm paralysis. As a druggable target present in many parasitic flatworms, TRPMPZQ is a promising target for a target-based screening campaign with the goal of discovering novel regulators of this channel complex. Here, we have optimized methods to miniaturize a Ca2+-based reporter assay for Schistosoma mansoni TRPMPZQ (Sm.TRPMPZQ) activity enabling a high throughput screening (HTS) approach. This methodology will enable further HTS efforts against Sm.TRPMPZQ as well as other flatworm ion channels. A pilot screen of ~16,000 compounds yielded a novel activator of Sm.TRPMPZQ, and numerous potential blockers. The new activator of Sm.TRPMPZQ represented a distinct chemotype to PZQ, but is a known chemical entity previously identified by phenotypic screening. The fact that a compound prioritized from a phenotypic screening campaign is revealed to act, like PZQ, as an Sm.TRPMPZQ agonist underscores the validity of TRPMPZQ as a druggable target for antischistosomal ligands.
Highlights
Over a billion people worldwide require chemotherapy for neglected tropical diseases (NTDs, [1])
Schistosomiasis, a disease caused by infection by parasitic flatworms known as schistosomes, is one of several NTDs targeted for elimination as a public health problem in the World Health Organization 2021–2030 NTD road map [1]
We recently discovered that PZQ activates a Ca2+-permeable ion channel in Schistosoma mansoni that belongs to the melastatin family of transient receptor potential (TRP) channels
Summary
Over a billion people worldwide require chemotherapy for neglected tropical diseases (NTDs, [1]). Schistosomiasis, a disease caused by infection by parasitic flatworms known as schistosomes, is one of several NTDs targeted for elimination as a public health problem in the World Health Organization 2021–2030 NTD road map [1]. Schistosomiasis, as well as several other parasitic flatworm infections [2], are treated using the anthelmintic drug praziquantel (PZQ). PZQ has remained an effective treatment for schistosomiasis over four decades of clinical use [3], underpinning recent mass drug administration (MDA) campaigns aimed at decreasing infections and morbidity in vulnerable populations. PZQ has several features that could be improved and the threat of drug resistance, potentially accelerated by the rollout of MDA initiatives, persists [4,5,6]
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