Journal article 1419 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
,
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 |
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2013
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| URI: | https://cronfa.swan.ac.uk/Record/cronfa15178 |
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| spelling |
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 0000-0001-7991-5040 Steven Kelly Steven Kelly true false 2013-07-08 FGMHL 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 Medicine, Health and Life Science - Faculty COLLEGE CODE FGMHL 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 0000-0001-7991-5040 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 |
| author_id_str_mv |
f066e233e8d0136c9f547b86fa43747f e563ed4e1c7db8d1e131fb78a5f8d0d5 5ccf81e5d5beedf32ef8d7c3d7ac6c8c b17cebaf09b4d737b9378a3581e3de93 |
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f066e233e8d0136c9f547b86fa43747f_***_Andrew Warrilow e563ed4e1c7db8d1e131fb78a5f8d0d5_***_Josie Parker 5ccf81e5d5beedf32ef8d7c3d7ac6c8c_***_Diane Kelly b17cebaf09b4d737b9378a3581e3de93_***_Steven Kelly |
| author |
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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Journal article |
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PLoS ONE |
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8 |
| container_issue |
6 |
| publishDate |
2013 |
| institution |
Swansea University |
| issn |
1932-6203 |
| doi_str_mv |
10.1371/journal.pone.0065928 |
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Faculty of Medicine, Health and Life Sciences |
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facultyofmedicinehealthandlifesciences |
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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 |
2013-12-31T03:17:18Z |
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1763750380180602880 |
| score |
11.016235 |