Please use this identifier to cite or link to this item: https://www.arca.fiocruz.br/handle/icict/29537
Title: CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM)
Authors: Debnath, Anjan
Calvet, Claudia M.
Jennings, Gareth
Zhou, Wenxu
Aksenov, Alexander
Luth, Madeline R.
Abagyan, Ruben
Nes, W. David
McKerrow, James H.
Podust, lLarissa M.
Affilliation: University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA / Fundação Oswaldo Cruz. Instituto Oswaldo Cruz. Laboratório de Ultraestrutura Celular. Rio de Janeiro, RJ, Brasil.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
Texas Tech University. Department of Chemistry & Biochemistry. Lubbock, Texas, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
Texas Tech University. Department of Chemistry & Biochemistry. Lubbock, Texas, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
University of California San Diego. Skaggs School of Pharmacy and Pharmaceutical Sciences. Center for Discovery and Innovation in Parasitic DiseasesLa Jolla. Center for Discovery and Innovation in Parasitic Diseases. CA, USA.
Abstract: Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered ªrareº (but likely underreported) the high mortality rate and lack of established success in treatment makes PAM a particularly devastating infection. In the absence of economic inducements to invest in development of anti-PAM drugs by the pharmaceutical industry, anti-PAM drug discovery largely relies on drug `repurposing'Ða cost effective strategy to apply known drugs for treatment of rare or neglected diseases. Similar to fungi, N. fowleri has an essential requirement for ergosterol, a building block of plasma and cell membranes. Disruption of sterol biosynthesis by small-molecule inhibitors is a validated interventional strategy against fungal pathogens of medical and agricultural importance. The N. fowleri genome encodes the sterol 14- demethylase (CYP51) target sharing ~35% sequence identity to fungal orthologues. The similarity of targets raises the possibility of repurposing anti-mycotic drugs and optimization of their usage for the treatment of PAM. In this work, we (i) systematically assessed the impact of anti-fungal azole drugs, known as conazoles, on sterol biosynthesis and viability of cultured N. fowleri trophozotes, (ii) identified the endogenous CYP51 substrate by mass spectrometry analysis of N. fowleri lipids, and (iii) analyzed the interactions between the recombinant CYP51 target and conazoles by UV-vis spectroscopy and x-ray crystallography. Collectively, the target-based and parasite-based data obtained in these studies validated CYP51 as a potentially `druggable' target in N. fowleri, and conazole drugs as the candidates for assessment in the animal model of PAM.
Keywords: drug
treatment
CYP51
primary amoebic meningoencephalitis
keywords: CYP51
meningoencefalite amebiana primária
Tratamento
Issue Date: 2017
Publisher: Public Library of Science
Citation: DEBNATH, Anjan; et al. CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM). PLoS Negl Trop Dis., v.11, n.12, e0006104, 24p, Dec.2017.
ISSN: 1935-2727
Copyright: open access
Appears in Collections:IOC - Artigos de Periódicos

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