Antibiotic Effects of Loperamide: Homology of Human Targets of Loperamide with Targets in Acanthamoeba spp
| Autor: | S. Sumayya Tariq, M. Mohsin Mannan, Zohaib Rana, H. R. Ahmad, Abdul Mannan Baig |
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| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Diarrhea Models Molecular Loperamide Calmodulin 030106 microbiology Protozoan Proteins Apoptosis Pharmacology Ligands 03 medical and health sciences chemistry.chemical_compound parasitic diseases Drug Discovery medicine Humans Pharmacology (medical) Propidium iodide Amebicides Amino Acid Sequence Molecular Targeted Therapy Trophozoites Receptor Acanthamoeba castellanii Voltage-dependent calcium channel biology Calcium channel Computational Biology General Medicine biology.organism_classification Calcium Channel Blockers Acanthamoeba Anti-Bacterial Agents Infectious Diseases chemistry Structural Homology Protein Receptors Opioid biology.protein Calcium Calcium Channels medicine.drug Protein Binding Signal Transduction |
| Zdroj: | Recent patents on anti-infective drug discovery. 12(1) |
| ISSN: | 2212-4071 |
| Popis: | BACKGROUND Loperamide is an anti-diarrheal drug prescribed for non-infectious diarrhea. The drug is an opioid receptor agonist, blocker of voltage-dependent calcium channel (Cav) and calmodulin (CaM) inhibitor on human cells. Loperamide has been reported to exert anti-amoebic effects against pathogenic strains of Acanthamoeba castellanii. OBJECTIVES The precise mode of antibiotic action, cellular target homology with human counterparts and the pattern of cell death induced by loperamide in Acanthamoeba castellanii remain to be established. Additionally, we attempt to establish the presence a primitive Cav in Acanthamoeba castellanii. METHODS Bioinformatics, 3D structural modelling, ligand binding predictions and apoptotic/ amoebicidal assays were used in this study to answer the above queries. Amino acid sequences and structural models were compared between human and A. castellanii proteins that are involved in the regulation of calcium (Ca+2) homeostasis. RESULTS Our results show that A. castellanii expresses similar, to near identical types of primitive calcium channels Cav Ac and CaM that are well known targets of loperamide in humans. The growth assays showed anti-amoebic effects of loperamide at different doses, both alone and in combinations with other Ca+2- CaM inhibitors. The synergistic actions of loperamide with haloperidol showed to be more amoebicidal than when either of them used alone. Imaging with Annexin V, Acridine orange and Propidium iodide showed apoptosis in A. castellanii at a dose of 100 µg/ml and necrosis at higher doses of 250 µg/ml. CONCLUSION Though, Acanthamoeba does not express a homolog of the human mu-opioid receptor, but does shows evidence of the homologs for other known human targets of loperamide that are involved in Ca+2 uptake and Ca+2 signal transduction pathways. This suggests optimization of similar drug interactions with these targets may be useful in developing new approaches to control the growth of this parasite and possibly the diseases caused by it. |
| Databáze: | OpenAIRE |
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