Journal article 1546 views
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy
Daotai Nie,
Eric K Hoobler,
Ganesha Rai,
Andrew Warrilow,
Steven C Perry,
Christopher J Smyrniotis,
Ajit Jadhav,
Anton Simeonov,
Josie Parker,
Diane Kelly,
David J Maloney,
Steven Kelly,
Theodore R Holman
PLoS ONE, Volume: 8, Issue: 6
Swansea University Authors: Andrew Warrilow, Josie Parker, Diane Kelly, Steven Kelly
Full text not available from this repository: check for access using links below.
DOI (Published version): 10.1371/journal.pone.0065928
Abstract
We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a pheny...
| Published in: | PLoS ONE |
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| ISSN: | 1932-6203 |
| Published: |
2013
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| Online Access: |
Check full text
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa15178 |
| first_indexed |
2013-07-23T12:13:58Z |
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| last_indexed |
2021-10-27T02:27:08Z |
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cronfa15178 |
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SURis |
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2021-10-26T16:57:21.1794016 v2 15178 2013-07-08 Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy f066e233e8d0136c9f547b86fa43747f Andrew Warrilow Andrew Warrilow true false e563ed4e1c7db8d1e131fb78a5f8d0d5 Josie Parker Josie Parker true false 5ccf81e5d5beedf32ef8d7c3d7ac6c8c Diane Kelly Diane Kelly true false b17cebaf09b4d737b9378a3581e3de93 Steven Kelly Steven Kelly true false 2013-07-08 We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM) and CYP51 (IC50 = 43 nM) in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 µM. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component Journal Article PLoS ONE 8 6 1932-6203 31 12 2013 2013-12-31 10.1371/journal.pone.0065928 COLLEGE NANME COLLEGE CODE Swansea University 2021-10-26T16:57:21.1794016 2013-07-08T14:05:36.6335867 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Daotai Nie 1 Eric K Hoobler 2 Ganesha Rai 3 Andrew Warrilow 4 Steven C Perry 5 Christopher J Smyrniotis 6 Ajit Jadhav 7 Anton Simeonov 8 Josie Parker 9 Diane Kelly 10 David J Maloney 11 Steven Kelly 12 Theodore R Holman 13 |
| title |
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy |
| spellingShingle |
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy Andrew Warrilow Josie Parker Diane Kelly Steven Kelly |
| title_short |
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy |
| title_full |
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy |
| title_fullStr |
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy |
| title_full_unstemmed |
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy |
| title_sort |
Discovery of a Novel Dual Fungal CYP51/Human 5-Lipoxygenase Inhibitor: Implications for Anti-Fungal Therapy |
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f066e233e8d0136c9f547b86fa43747f e563ed4e1c7db8d1e131fb78a5f8d0d5 5ccf81e5d5beedf32ef8d7c3d7ac6c8c b17cebaf09b4d737b9378a3581e3de93 |
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f066e233e8d0136c9f547b86fa43747f_***_Andrew Warrilow e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker 5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly |
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Andrew Warrilow Josie Parker Diane Kelly Steven Kelly |
| author2 |
Daotai Nie Eric K Hoobler Ganesha Rai Andrew Warrilow Steven C Perry Christopher J Smyrniotis Ajit Jadhav Anton Simeonov Josie Parker Diane Kelly David J Maloney Steven Kelly Theodore R Holman |
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PLoS ONE |
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2013 |
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Swansea University |
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1932-6203 |
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10.1371/journal.pone.0065928 |
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Faculty of Medicine, Health and Life Sciences |
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Faculty of Medicine, Health and Life Sciences |
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Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine |
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| description |
We report the discovery of a novel dual inhibitor targeting fungal sterol 14α-demethylase (CYP51 or Erg11) and human 5-lipoxygenase (5-LOX) with improved potency against 5-LOX due to its reduction of the iron center by its phenylenediamine core. A series of potent 5-LOX inhibitors containing a phenylenediamine core, were synthesized that exhibit nanomolar potency and >30-fold selectivity against the LOX paralogs, platelet-type 12-human lipoxygenase, reticulocyte 15-human lipoxygenase type-1, and epithelial 15-human lipoxygenase type-2, and >100-fold selectivity against ovine cyclooxygenase-1 and human cyclooxygnease-2. The phenylenediamine core was then translated into the structure of ketoconazole, a highly effective anti-fungal medication for seborrheic dermatitis, to generate a novel compound, ketaminazole. Ketaminazole was found to be a potent dual inhibitor against human 5-LOX (IC50 = 700 nM) and CYP51 (IC50 = 43 nM) in vitro. It was tested in whole blood and found to down-regulate LTB4 synthesis, displaying 45% inhibition at 10 µM. In addition, ketaminazole selectively inhibited yeast CYP51 relative to human CYP51 by 17-fold, which is greater selectivity than that of ketoconazole and could confer a therapeutic advantage. This novel dual anti-fungal/anti-inflammatory inhibitor could potentially have therapeutic uses against fungal infections that have an anti-inflammatory component |
| published_date |
2013-12-31T18:31:40Z |
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1821431352586665984 |
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11.047609 |