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CYP51 is an essential drug target for the treatment of primary amoebic meningoencephalitis (PAM).

Abstract Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a free-living amoeba that occasionally infects humans. While considered "rare" (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'-a 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.
PMID
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Authors

Mayor MeshTerms
Keywords
Journal Title plos neglected tropical diseases
Publication Year Start




PMID- 29284029
OWN - NLM
STAT- In-Data-Review
LR  - 20171228
IS  - 1935-2735 (Electronic)
IS  - 1935-2727 (Linking)
VI  - 11
IP  - 12
DP  - 2017 Dec
TI  - CYP51 is an essential drug target for the treatment of primary amoebic
      meningoencephalitis (PAM).
PG  - e0006104
LID - 10.1371/journal.pntd.0006104 [doi]
AB  - Primary Amoebic Meningoencephalitis (PAM) is caused by Naegleria fowleri, a
      free-living amoeba that occasionally infects humans. While considered "rare" (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'-a 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.
FAU - Debnath, Anjan
AU  - Debnath A
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Calvet, Claudia M
AU  - Calvet CM
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
AD  - Cellular Ultrastructure Laboratory, Oswaldo Cruz Institute, FIOCRUZ, Rio de
      Janeiro, RJ, Brazil.
FAU - Jennings, Gareth
AU  - Jennings G
AUID- ORCID: http://orcid.org/0000-0001-7986-8491
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Zhou, Wenxu
AU  - Zhou W
AUID- ORCID: http://orcid.org/0000-0003-0487-1818
AD  - Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas,
      United States of America.
FAU - Aksenov, Alexander
AU  - Aksenov A
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Luth, Madeline R
AU  - Luth MR
AUID- ORCID: http://orcid.org/0000-0001-9059-1200
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Abagyan, Ruben
AU  - Abagyan R
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Nes, W David
AU  - Nes WD
AD  - Department of Chemistry & Biochemistry, Texas Tech University, Lubbock, Texas,
      United States of America.
FAU - McKerrow, James H
AU  - McKerrow JH
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
FAU - Podust, Larissa M
AU  - Podust LM
AUID- ORCID: http://orcid.org/0000-0002-8537-8760
AD  - Center for Discovery and Innovation in Parasitic Diseases, Skaggs School of
      Pharmacy and Pharmaceutical Sciences, University of California San Diego, La
      Jolla, California, United States of America.
LA  - eng
PT  - Journal Article
DEP - 20171228
PL  - United States
TA  - PLoS Negl Trop Dis
JT  - PLoS neglected tropical diseases
JID - 101291488
EDAT- 2017/12/29 06:00
MHDA- 2017/12/29 06:00
CRDT- 2017/12/29 06:00
PHST- 2017/08/07 00:00 [received]
PHST- 2017/11/08 00:00 [accepted]
PHST- 2017/12/29 06:00 [entrez]
PHST- 2017/12/29 06:00 [pubmed]
PHST- 2017/12/29 06:00 [medline]
AID - 10.1371/journal.pntd.0006104 [doi]
AID - PNTD-D-17-01265 [pii]
PST - epublish
SO  - PLoS Negl Trop Dis. 2017 Dec 28;11(12):e0006104. doi:
      10.1371/journal.pntd.0006104. eCollection 2017 Dec.