Advances in our understanding of nematode ion channels as potential anthelmintic targets

Choudhary, Shivani; Kashyap, Sudhanva S.; Martin, R. J.; Robertson, Alan P.

doi:10.1016/j.ijpddr.2021.12.001

Cited by 14 publications

(14 citation statements)

References 403 publications

(739 reference statements)

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“…C. elegans ACR-16 shows similarities to human α7 in that it assembles as a homomeric pentamer and has 60% sequence similarity (45% identity) according to Clustal omega. ACR-16 is the founding member of a large family of related C. elegans nAChRs [ 61 , 62 , 63 ]. However, the SAP motif is not conserved in other members of the ACR-16 sub-family [ 64 ] such as ACR-19.…”

Section: Resultsmentioning

confidence: 99%

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

Loring

2022

Molecules

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The process of how multimeric transmembrane proteins fold and assemble in the endoplasmic reticulum is not well understood. The alpha7 nicotinic receptor (α7 nAChR) is a good model for multimeric protein assembly since it has at least two independent and specialized chaperones: Resistance to Inhibitors of Cholinesterase 3 (RIC-3) and Nicotinic Acetylcholine Receptor Regulator (NACHO). Recent cryo-EM and NMR data revealed structural features of α7 nAChRs. A ser-ala-pro (SAP) motif precedes a structurally important but unique “latch” helix in α7 nAChRs. A sampling of α7 sequences suggests the SAP motif is conserved from C. elegans to humans, but the latch sequence is only conserved in vertebrates. How RIC-3 and NACHO facilitate receptor subunits folding into their final pentameric configuration is not known. The artificial intelligence program AlphaFold2 recently predicted structures for NACHO and RIC-3. NACHO is highly conserved in sequence and structure across species, but RIC-3 is not. This review ponders how different intrinsically disordered RIC-3 isoforms from C. elegans to humans interact with α7 nAChR subunits despite having little sequence homology across RIC-3 species. Two models from the literature about how RIC-3 assists α7 nAChR assembly are evaluated considering recent structural information about the receptor and its chaperones.

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Section: Resultsmentioning

confidence: 99%

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

Loring

2022

Molecules

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“…However, in roundworms, albendazole and other benzimidazoles bind to tubulins of susceptible worms, preventing their incorporation into microtubes. As cytoplasmic microtubules are critical for promoting glucose uptake, the glycogen stores of the parasites are depleted, leading to the death of the parasites ( 15 , 16 ). Interestingly, N -(4-methoxyphenyl)pentanamide demonstrated anthelmintic activity similar to that of albendazole, and hence, this study may provide the basis for the future development of new albendazole preparations.…”

Section: Resultsmentioning

confidence: 99%

N -(4-Methoxyphenyl)Pentanamide, a Simplified Derivative of Albendazole, Displays Anthelmintic Properties against the Nematode Toxocara canis

et al. 2022

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“…Except for moxidectin and salamectin, all the anthelmintics found to be active against A. cantonensis L1 larvae are in the WHO Model Lists of Essential Medicines. Most anthelmintics have a broad spectrum of activity ( Geary et al, 2010 ; Choudhary et al, 2022 ). However, the usefulness of any anthelmintic is limited by the characteristics of the parasite (e.g., susceptibility of the life stage, or susceptibility to the drugs), and these compounds have specific activities for each species ( Geary et al, 2010 ; Keiser and Häberli, 2021 ).…”

Section: Discussionmentioning

confidence: 99%

“…In A. cantonensis , anthelmintics mode of action are unknown. However, in nematodes, the mode of actions and targets for anthelmintic drugs have been described ( Geary et al, 2010 ; Wit et al, 2021 ; Choudhary et al, 2022 ). Benzimidazoles are predicted to selectively bind near the colchicine binding site of β -tubulin.…”

Section: Discussionmentioning

confidence: 99%

Susceptibility of Angiostrongylus cantonensis Larvae to Anthelmintic Drugs

et al. 2022

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Human helminthiasis affects approximately one in five people in the world and disproportionally affects the poorest and most deprived communities. Human angiostrongyliasis, caused by nematode Angiostrongylus cantonensis, is a neglected emerging disease with escalating importance worldwide. Chemotherapy is the main control method for helminthiasis, but the therapeutic arsenal is limited. This study aimed to evaluate the antiparasitic and molecular properties of the major available anthelmintic drugs against A. cantonensis in vitro. The first-stage larvae (L1), isolated from feces of an A. cantonensis-infected rat, were exposed to a set of 12 anthelmintic drugs in vitro. The larvae were monitored, and the concentration- and time-dependent viability alterations were determined. From 12 anthelmintic drugs, six (ivermectin, salamectin, moxidectin, pyrantel pamoate, albendazole and levamisole) were identified to affect the viability of A. cantonensis. The macrocyclic lactones (ivermectin, salamectin, moxidectin) and the imidazothiazole levamisole, were the most effective drugs, with IC50 ranging from 2.2 to 2.9 µM and a rapid onset of action. Albendazole, the most widely used anthelmintic in humans, had a slower onset of action, but an IC50 of 11.3 µM was achieved within 24 h. Molecular properties studies suggest that a less lipophilic character and low molecular weight could be favorable for the biological activity of the non-macrocyclic molecules. Collectively, our study revealed that macrocyclic lactones, levamisole, pyrantel pamoate, and albendazole are important anthelmintic agents against A. cantonensis. The results of this in vitro study also suggest that A. cantonensis L1 may be a particularly sensitive and useful model for anthelmintic studies.

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Advances in our understanding of nematode ion channels as potential anthelmintic targets

Cited by 14 publications

References 403 publications

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

Speculation on How RIC-3 and Other Chaperones Facilitate α7 Nicotinic Receptor Folding and Assembly

N -(4-Methoxyphenyl)Pentanamide, a Simplified Derivative of Albendazole, Displays Anthelmintic Properties against the Nematode Toxocara canis

Susceptibility of Angiostrongylus cantonensis Larvae to Anthelmintic Drugs

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