Identification of novel modulators of a schistosome transient receptor potential channel targeted by praziquantel
| Autor: | Louis Scampavia, Claudia M. Rohr, Timothy P. Spicer, Evgeny G. Chulkov, Sang-Kyu Park, Jonathan S. Marchant, Emery Smith, Nawal A. Yahya |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Male
Physiology Flatworms RC955-962 Druggability Drug Evaluation Preclinical Biochemistry Ion Channels Praziquantel Transient receptor potential channel Mice Transient Receptor Potential Channels Arctic medicine. Tropical medicine Medicine and Health Sciences Anthelmintic Anthelmintics Physics Eukaryota Helminth Proteins Schistosoma mansoni Electrophysiology Infectious Diseases Physical Sciences Neglected tropical diseases Schistosoma Cell lines Female Public aspects of medicine RA1-1270 Biological cultures medicine.drug Research Article Phenotypic screening Biophysics Neurophysiology Computational biology Library Screening Biology Research and Analysis Methods Transfection Helminths parasitic diseases medicine Animals Humans Molecular Biology Techniques Molecular Biology Pharmacology Drug Screening Molecular Biology Assays and Analysis Techniques HEK 293 cells Public Health Environmental and Occupational Health Organisms Biology and Life Sciences Proteins biology.organism_classification Invertebrates Schistosomiasis mansoni Calcium Zoology Neuroscience |
| Zdroj: | PLoS Neglected Tropical Diseases, Vol 15, Iss 11 (2021) PLoS Neglected Tropical Diseases PLoS Neglected Tropical Diseases, Vol 15, Iss 11, p e0009898 (2021) |
| ISSN: | 1935-2735 1935-2727 |
| Popis: | 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. Author summary The drug praziquantel is used to treat diseases caused by parasitic flatworms. Praziquantel is an old drug, and there is a need to identify novel treatments that retain desirable features and improve weaknesses in the mode of PZQ action. One way to do this is to identify new drugs that exploit vulnerabilities in the same drug target but work in slightly differently ways. Here, we have optimized high throughput screening methods to pharmacologically profile a parasitic flatworm ion channel targeted by PZQ. We have identified several new chemical structures that interact with this channel complex. These ligands provide new opportunity for developing tools to manipulate flatworm biology and potentially new trajectories for anthelmintic drug development. |
| Databáze: | OpenAIRE |
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