Bioinformatic Insights on Target Receptors of Amiodarone in Human and Acanthamoeba castellanii

Baig, Abdul Mannan; Rana, Zohaib; Tariq, Sumayya; Ahmad, Hamna

doi:10.2174/1871526517666170622075154

Cited by 4 publications

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“…As previously reported (Baig et al., 2017), we found that both ACA1_270170 and ACA1_092610 had remarkable amino acid sequence homologies with TPC1, human L‐type Cav and P/Q type Cav as evident on multiple sequence alignments of these amoebal proteins with the aforementioned human types of Cav's (Figures ). We explored the evolutionary origins of family Ion_Trans and its subtypes TPC ion channel for its distribution in species and found that this family, and its subtypes were present in species as remote as prokaryotes, fungi, and uncharacterized unicellular eukaryotes (Finn et al., ) (Figures , a).…”

Section: Discussionsupporting

confidence: 83%

“…Although some recent studies have reported targets of drugs like amiodarone on Na‐K channels in Acanthamoeba (Baig, Rana et al, 2017) and loperamide on human Cav like ACA1_167020 (Baig et al, 2017); to the best of our knowledge, this is the first time that transcriptomics, metagenomics, bioinformatic computational tools, and ligand binding attributes with experimentations have evidenced for origins and placement of Acanthamoeba Cav like proteins in the specie tree and provide clue toward them being the targets of amlodipine in Acanthamoeba spp.…”

Section: Discussionmentioning

confidence: 92%

“…A major transporter cation channel family protein ACA1_167020 ( Acanthamoeba castellanii str. Neff‐accession # ELR18842) in a previous study has been compared with human Cav to find its homology with two‐pore channels (TPC), L‐type Cav, and other diverse types of Cav (Baig et al., 2017). The latter study found effects of loperamide on calmodulin and many other types of Cav in the in vitro cytotoxic assays.…”

Section: Introductionmentioning

confidence: 99%

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Evidence of human‐like Ca²⁺ channels and effects of Ca²⁺ channel blockers in Acanthamoeba castellanii

et al. 2019

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The evolution of voltage-gated calcium channel (Cav) in eukaryotes is an area of interest for biologists worldwide. The CLAN CL0030 and its family Ion_Trans 2 PF 07885 have been known to be present in prokaryotes, but the origin of these ion channels in Acanthamoeba spp. is yet to be determined. We inferred the origin of primitive forms of two-pore channels like proteins, human-like Cav 1.1 of L-type, and Cav subunit alpha-2/delta-1 in Acanthamoeba spp. early during evolution. By in-depth investigation into genomics, transcriptomics, use of bioinformatics tools and experimentations done with drugs like amlodipine and gabapentin on Acanthamoeba spp., we show the evidence of primitive forms of these channels in this protist pathogen.Genomics and transcriptomics of proteins ACA1_167020, 092610, and 270170 reflected their cellular expression in Acanthamoeba spp. We performed amino acid sequence homology, 3D structural modeling, ligand binding predictions, and dockings. Bioinformatics and 3D structural models show similarities between ACA1_167020, 092610, 270170, and different types of known human Cav. We show amoebicidal effects of amlodipine and gabapentin on Acanthamoeba spp., which can help design their structural analogs to target pathogenic genotypes of Acanthamoeba in diseases like Acanthamoeba keratitis and granulomatous amoebic encephalitis.

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Section: Discussionsupporting

confidence: 83%

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

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Evidence of human‐like Ca²⁺ channels and effects of Ca²⁺ channel blockers in Acanthamoeba castellanii

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“…As seen in this study, the encysted amoeba shifts its metabolic preference from one nutrient to another when a particular pathway like the activity of glucoside is targeted ( Figures 5 and 6) channels and preventing the formation of Ca 2+ -Calmodulin complex via specific drugs like Loperamide, Amlodipine and Prochlorperazine, the encysted amoebae were not able to survive in the encysted state (Figure 7a-c). For Loperamide, which is an inhibitor of voltage-gated calcium channels (Cav) and calmodulin (CaM) (Laurence, Bruce, Björn, 2011) it has been recently shown that it has amoebicidal effects on Acanthamoeba trophozoites (Figure 5b) are achieved by targeting a human-like Cav called CavAc (Baig et al, 2017). The Ca 2+ ions channels are also the targets of Amlodipine that are known to target Cav1.1, Cav1.2 subtypes, and carbonic anhydrase that has proven to be amoebicidal for the encysted amoeba as well (Figure 7c).…”

Section: Discussionmentioning

confidence: 99%

‘Targeting the feast of a sleeping beast’: Nutrient and mineral dependencies of encysted Acanthamoeba castellanii

et al. 2020

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Acanthamoeba spp. cause a corneal infection, Acanthamoeba keratitis (AK), and a cerebral infection, granulomatous amoebic encephalitis (GAE). Though aggressive chemotherapy has been able to kill the active trophozoite form of Acanthamoeba, the encysted form of this parasite has remained problematic to resist physiological concentrations of drugs. The emergence of encysted amoeba into active trophozoite form poses a challenge to eradicate this parasite. Acanthamoeba trophozoites have active metabolic machinery that furnishes energy in the form of ATPs by subjecting carbohydrates and lipids to undergo pathways including glycolysis and beta-oxidation of free fatty acids, respectively. However, very little is known about the metabolic preferences and dependencies of an encysted trophozoite on minerals or potential nutrients that it consumes to live in an encysted state. Here, we investigate the metabolic and nutrient preferences of the encysted trophozoite of Acanthamoeba castellanii and the possibility to target them by drugs that act on calcium ion dependencies of the encysted amoeba. The experimental assays, immunostaining coupled with bioinformatics tools show that the encysted Acanthamoeba uses diverse nutrient pathways to obtain energy in the quiescent encysted state. These findings highlight potential pathways that can be targeted in eradicating amoebae cysts successfully. K E Y W O R D S Acanthamoeba, Ca 2+ ion channels, cysticidal drugs, cysts, encystation, encysted Acanthamoeba, metabolism How to cite this article: Baig AM, Khan NA, Katyara P, et al. 'Targeting the feast of a sleeping beast': Nutrient and mineral dependencies of an encysted

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“…In the present study, for the first time we investigated the role of ion transporters in sensory perception in the cyst stage of A. castellanii belonging to the T4 genotype. Based on the genome information, the presence of potassium ion transporters has been suggested [15]. However, their functional role in phenotypic switching is missing.…”

Section: Introductionmentioning

confidence: 99%

Novel insights into the potential role of ion transport in sensory perception in Acanthamoeba

et al. 2019

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BackgroundAcanthamoeba is well known to produce a blinding keratitis and serious brain infection known as encephalitis. Effective treatment is problematic, and can continue up to a year, and even then, recurrence can ensue. Partly, this is due to the capability of vegetative amoebae to convert into resistant cysts. Cysts can persist in an inactive form for decades while retaining their pathogenicity. It is not clear how Acanthamoeba cysts monitor environmental changes, and determine favourable conditions leading to their emergence as viable trophozoites.MethodsThe role of ion transporters in the encystation and excystation of Acanthamoeba remains unclear. Here, we investigated the role of sodium, potassium and calcium ion transporters as well as proton pump inhibitors on A. castellanii encystation and excystation and their effects on trophozoites.ResultsRemarkably 3′,4′-dichlorobenzamil hydrochloride a sodium–calcium exchange inhibitor, completely abolished excystation of Acanthamoeba. Furthermore, lanthanum oxide and stevioside hydrate, both potassium transport inhibitors, resulted in the partial inhibition of Acanthamoeba excystation. Conversely, none of the ion transport inhibitors affected encystation or had any effects on Acanthamoeba trophozoites viability.ConclusionsThe present study indicates that ion transporters are involved in sensory perception of A. castellanii suggesting their value as potential therapeutic targets to block cellular differentiation that presents a significant challenge in the successful prognosis of Acanthamoeba infections.

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Bioinformatic Insights on Target Receptors of Amiodarone in Human and Acanthamoeba castellanii

Cited by 4 publications

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Evidence of human‐like Ca²⁺ channels and effects of Ca²⁺ channel blockers in Acanthamoeba castellanii

Evidence of human‐like Ca²⁺ channels and effects of Ca²⁺ channel blockers in Acanthamoeba castellanii

‘Targeting the feast of a sleeping beast’: Nutrient and mineral dependencies of encysted Acanthamoeba castellanii

Novel insights into the potential role of ion transport in sensory perception in Acanthamoeba

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Bioinformatic Insights on Target Receptors of Amiodarone in Human and Acanthamoeba castellanii

Cited by 4 publications

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Evidence of human‐like Ca2+ channels and effects of Ca2+ channel blockers in Acanthamoeba castellanii

Evidence of human‐like Ca2+ channels and effects of Ca2+ channel blockers in Acanthamoeba castellanii

‘Targeting the feast of a sleeping beast’: Nutrient and mineral dependencies of encysted Acanthamoeba castellanii

Novel insights into the potential role of ion transport in sensory perception in Acanthamoeba

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Evidence of human‐like Ca²⁺ channels and effects of Ca²⁺ channel blockers in Acanthamoeba castellanii

Evidence of human‐like Ca²⁺ channels and effects of Ca²⁺ channel blockers in Acanthamoeba castellanii