ABSTRACT
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.
Subject(s)
Acanthamoeba castellanii/metabolism , Amebicides/chemistry , Calcium Channel Blockers/chemistry , Calcium Channels/metabolism , Acanthamoeba castellanii/drug effects , Amebicides/metabolism , Amebicides/pharmacology , Amino Acid Sequence , Amlodipine/chemistry , Amlodipine/metabolism , Amlodipine/pharmacology , Binding Sites , Calcium Channel Blockers/metabolism , Calcium Channel Blockers/pharmacology , Calcium Channels/chemistry , Carbonic Anhydrase I/chemistry , Carbonic Anhydrase I/metabolism , Gabapentin/chemistry , Gabapentin/metabolism , Gabapentin/pharmacology , Humans , Hydrogen Bonding , Ligands , Molecular Docking Simulation , Protein Structure, Tertiary , Sequence AlignmentABSTRACT
Neurotropic parasitic amoebal infections have imposed an enormous challenge to chemotherapy in patients who fall victims to the infections caused by them. Conventional antibiotics that are given to treat these infections have a low patient compliance because of the serious adverse effects that are associated with their use. Additionally, the growing incidence of the development of drug resistance by the neurotropic parasites like Naegleria fowleri, Balamuthia mandrillaris, and Acanthamoeba spp has made the drug therapy more challenging. Recent studies have reported some cellular targets in the neurotropic parasitic Acanthamoeba that are used as receptors by human neurotransmitters like acetylcholine. This Viewpoint attempts to highlight the novel methodologies that use drug assays and structural modeling to uncover cellular targets of diverse groups of drugs and the safety issues of the drugs proposed for their use in brain infections caused by the neurotropic parasitic amoebae.
