Pharmacological Profiling of a Brugia malayi Muscarinic Acetylcholine Receptor as a Putative Antiparasitic Target.
Pharmacological Profiling of a Brugia malayi Muscarinic Acetylcholine Receptor as a Putative Antiparasitic Target.
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马来棕树毒蕈碱乙酰胆碱受体作为推测的抗寄生虫靶点的药理学分析。
DOI：
10.1128/aac.01188-22
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发表时间：
2023-01-24
影响因子：
4.9
通讯作者：
Zamanian, Mostafa
中科院分区：
文献类型：
--
作者：
Gallo, Kendra J.;Wheeler, Nicolas J.;Elmi, Abdifatah M.;Airs, Paul M.;Zamanian, Mostafa
关键词：
The diversification of anthelmintic targets and mechanisms of action will help ensure the sustainable control of nematode infections in response to the growing threat of drug resistance. G protein-coupled receptors (GPCRs) are established drug targets in human medicine but remain unexploited as anthelmintic substrates despite their important roles in nematode neuromuscular and physiological processes. Bottlenecks in exploring the druggability of parasitic nematode GPCRs include a limited helminth genetic toolkit and difficulties establishing functional heterologous expression. In an effort to address some of these challenges, we profile the function and pharmacology of muscarinic acetylcholine receptors in the human parasite Brugia malayi, an etiological agent of human lymphatic filariasis. While acetylcholine-gated ion channels are intensely studied as targets of existing anthelmintics, comparatively little is known about metabotropic receptor contributions to parasite cholinergic signaling. Using multivariate phenotypic assays in microfilariae and adults, we show that nicotinic and muscarinic compounds disparately affect parasite fitness traits. We identify a putative G protein-linked acetylcholine receptor of B. malayi (Bma-GAR-3) that is highly expressed across intramammalian life stages and adapt spatial RNA in situ hybridization to map receptor transcripts to critical parasite tissues. Tissue-specific expression of Bma-gar-3 in Caenorhabditis elegans (body wall muscle, sensory neurons, and pharynx) enabled receptor deorphanization and pharmacological profiling in a nematode physiological context. Finally, we developed an image-based feeding assay as a reporter of pharyngeal activity to facilitate GPCR screening in parasitized strains. We expect that these receptor characterization approaches and improved knowledge of GARs as putative drug targets will further advance the study of GPCR biology across medically important nematodes.
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DOI：
10.1515/acve-2017-0013
发表时间：
2017-06
期刊：
Acta veterinaria
影响因子：
--
作者：
Abongwa M;Martin RJ;Robertson AP
通讯作者：
Robertson AP
影响因子：
3.8
作者：
Ballesteros C;Tritten L;O'Neill M;Burkman E;Zaky WI;Xia J;Moorhead A;Williams SA;Geary TG
通讯作者：
Geary TG
影响因子：
4
作者：
Kimber MJ;Sayegh L;El-Shehabi F;Song C;Zamanian M;Woods DJ;Day TA;Ribeiro P
通讯作者：
Ribeiro P
影响因子：
1.5
作者：
Abubucker, Sahar;Martin, John;Mitreva, Makedonka
通讯作者：
Mitreva, Makedonka
影响因子：
1.5
作者：
Cook, A;Aptel, N;Wolstenholme, A
通讯作者：
Wolstenholme, A