Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase and application of statins as a novel effective therapeutic approach against Acanthamoeba infections
| Autor: | Jacob Lorenzo-Morales, Sutherland K. Maciver, Isabel Fuentes, José Manuel García-Castellano, Basilio Valladares, Brendan J. Loftus, Rubén P. Machín, Carmen María Martín-Navarro, Atteneri López-Arencibia, José E. Piñero |
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| Rok vydání: | 2012 |
| Předmět: |
Small interfering RNA
Molecular Sequence Data Protozoan Proteins Mevalonic Acid Reductase Microbiology chemistry.chemical_compound Inhibitory Concentration 50 RNA interference Catalytic Domain parasitic diseases medicine Pharmacology (medical) Experimental Therapeutics Amino Acid Sequence Granulomatous amoebic encephalitis RNA Small Interfering Cells Cultured Cell Proliferation Enzyme Assays Pharmacology Ergosterol Acanthamoeba castellanii biology medicine.disease biology.organism_classification Acanthamoeba Infectious Diseases Acanthamoeba keratitis chemistry Hydroxymethylglutaryl-CoA-Reductases NADP-dependent Protozoa Acyl Coenzyme A Hydroxymethylglutaryl-CoA Reductase Inhibitors |
| Zdroj: | Maria Martin-Navarro, C, Lorenzo-Morales, J, Machin, R P, Lopez-Arencibia, A, Manuel Garcia-Castellano, J, de Fuentes, I, Loftus, B, Maciver, S K, Valladares, B & Pineroa, J E 2013, ' Inhibition of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase and Application of Statins as a Novel Effective Therapeutic Approach against Acanthamoeba Infections ', Antimicrobial Agents and Chemotherapy, vol. 57, no. 1, pp. 375-381 . https://doi.org/10.1128/AAC.01426-12 |
| ISSN: | 1098-6596 |
| DOI: | 10.1128/AAC.01426-12 |
| Popis: | Acanthamoeba is an opportunistic pathogen in humans, whose infections most commonly manifest as Acanthamoeba keratitis or, more rarely, granulomatous amoebic encephalitis. Although there are many therapeutic options for the treatment of Acanthamoeba , they are generally lengthy and/or have limited efficacy. Therefore, there is a requirement for the identification, validation, and development of novel therapeutic targets against these pathogens. Recently, RNA interference (RNAi) has been widely used for these validation purposes and has proven to be a powerful tool for Acanthamoeba therapeutics. Ergosterol is one of the major sterols in the membrane of Acanthamoeba . 3-Hydroxy-3-methylglutaryl–coenzyme A (HMG-CoA) reductase is an enzyme that catalyzes the conversion of HMG-CoA to mevalonate, one of the precursors for the production of cholesterol in humans and ergosterol in plants, fungi, and protozoa. Statins are compounds which inhibit this enzyme and so are promising as chemotherapeutics. In order to validate whether this enzyme could be an interesting therapeutic target in Acanthamoeba , small interfering RNAs (siRNAs) against HMG-CoA were developed and used to evaluate the effects induced by the inhibition of Acanthamoeba HMG-CoA. It was found that HMG-CoA is a potential drug target in these pathogenic free-living amoebae, and various statins were evaluated in vitro against three clinical strains of Acanthamoeba by using a colorimetric assay, showing important activities against the tested strains. We conclude that the targeting of HMG-CoA and Acanthamoeba treatment using statins is a novel powerful treatment option against Acanthamoeba species in human disease. |
| Databáze: | OpenAIRE |
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