Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding
The regulation of vitamin D<sub>3</sub> actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D<sub>3</sub>) and 1,25-dihydroxycholecalciferol (1,25(OH)<sub>2</...
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MDPI AG
2022-07-01
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| Series: | Biomolecules |
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| Online Access: | https://www.mdpi.com/2218-273X/12/7/960 |
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| author | Ali K. Alshabrawy Yingjie Cui Cyan Sylvester Dongqing Yang Emilio S. Petito Kate R. Barratt Rebecca K. Sawyer Jessica K. Heatlie Ruhi Polara Matthew J. Sykes Gerald J. Atkins Shane M. Hickey Michael D. Wiese Andrea M. Stringer Zhaopeng Liu Paul H. Anderson |
| author_facet | Ali K. Alshabrawy Yingjie Cui Cyan Sylvester Dongqing Yang Emilio S. Petito Kate R. Barratt Rebecca K. Sawyer Jessica K. Heatlie Ruhi Polara Matthew J. Sykes Gerald J. Atkins Shane M. Hickey Michael D. Wiese Andrea M. Stringer Zhaopeng Liu Paul H. Anderson |
| author_sort | Ali K. Alshabrawy |
| collection | DOAJ |
| description | The regulation of vitamin D<sub>3</sub> actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D<sub>3</sub>) and 1,25-dihydroxycholecalciferol (1,25(OH)<sub>2</sub>D<sub>3</sub>), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D<sub>3</sub> contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 <i>O</i>-methyloxime analogue of vitamin D<sub>3</sub> (<b>VD1-6</b>) to have specific CYP24A1 inhibitory properties. <b>VD1-6</b> did not bind to the vitamin D receptor (VDR) in concentrations up to 10<sup>−7</sup> M, assessed by a VDR binding assay. The absence of VDR binding by <b>VD1-6</b> was confirmed in human embryonic kidney HEK293T cultures through the lack of <i>CYP24A1</i> induction. However, in silico docking experiments demonstrated that <b>VD1-6</b> was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)<sub>2</sub>D<sub>3</sub>. The inhibition of CYP24A1 by <b>VD1-6</b> was also evident by the synergistic potentiation of 1,25(OH)<sub>2</sub>D<sub>3</sub>-mediated transcription and reduced 1,25(OH)<sub>2</sub>D<sub>3</sub> catabolism over 24 h. A further indication of CYP24A1 inhibition by <b>VD1-6</b> was the reduced accumulation of the 24,25(OH)D<sub>3</sub>, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of <b>VD1-6</b> and its potential for testing as an alternative therapeutic candidate for treating SHPT. |
| first_indexed | 2024-03-09T03:39:29Z |
| format | Article |
| id | doaj.art-75b2b95d595343a397f3a5c7ac9b04d2 |
| institution | Directory Open Access Journal |
| issn | 2218-273X |
| language | English |
| last_indexed | 2024-03-09T03:39:29Z |
| publishDate | 2022-07-01 |
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| record_format | Article |
| series | Biomolecules |
| spelling | doaj.art-75b2b95d595343a397f3a5c7ac9b04d22023-12-03T14:43:36ZengMDPI AGBiomolecules2218-273X2022-07-0112796010.3390/biom12070960Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor BindingAli K. Alshabrawy0Yingjie Cui1Cyan Sylvester2Dongqing Yang3Emilio S. Petito4Kate R. Barratt5Rebecca K. Sawyer6Jessica K. Heatlie7Ruhi Polara8Matthew J. Sykes9Gerald J. Atkins10Shane M. Hickey11Michael D. Wiese12Andrea M. Stringer13Zhaopeng Liu14Paul H. Anderson15UniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaCentre for Orthopaedic and Trauma Research, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaCentre for Orthopaedic and Trauma Research, Faculty of Health and Medical Sciences, The University of Adelaide, Adelaide, SA 5005, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaDepartment of Medicinal Chemistry, Key Laboratory of Chemical Biology (Ministry of Education), School of Pharmaceutical Sciences, Cheeloo College of Medicine, Shandong University, Jinan 250012, ChinaUniSA Clinical and Health Sciences, Health and Biomedical Innovation, University of South Australia, Adelaide, SA 5001, AustraliaThe regulation of vitamin D<sub>3</sub> actions in humans occurs mainly through the Cytochrome P450 24-hydroxylase (CYP24A1) enzyme activity. CYP24A1 hydroxylates both 25-hydroxycholecalciferol (25(OH)D<sub>3</sub>) and 1,25-dihydroxycholecalciferol (1,25(OH)<sub>2</sub>D<sub>3</sub>), which is the first step of vitamin D catabolism. An abnormal status of the upregulation of CYP24A1 occurs in many diseases, including chronic kidney disease (CKD). CYP24A1 upregulation in CKD and diminished activation of vitamin D<sub>3</sub> contribute to secondary hyperparathyroidism (SHPT), progressive bone deterioration, and soft tissue and cardiovascular calcification. Previous studies have indicated that CYP24A1 inhibition may be an effective strategy to increase endogenous vitamin D activity and decrease SHPT. This study has designed and synthesized a novel C-24 <i>O</i>-methyloxime analogue of vitamin D<sub>3</sub> (<b>VD1-6</b>) to have specific CYP24A1 inhibitory properties. <b>VD1-6</b> did not bind to the vitamin D receptor (VDR) in concentrations up to 10<sup>−7</sup> M, assessed by a VDR binding assay. The absence of VDR binding by <b>VD1-6</b> was confirmed in human embryonic kidney HEK293T cultures through the lack of <i>CYP24A1</i> induction. However, in silico docking experiments demonstrated that <b>VD1-6</b> was predicted to have superior binding to CYP24A1, when compared to that of 1,25(OH)<sub>2</sub>D<sub>3</sub>. The inhibition of CYP24A1 by <b>VD1-6</b> was also evident by the synergistic potentiation of 1,25(OH)<sub>2</sub>D<sub>3</sub>-mediated transcription and reduced 1,25(OH)<sub>2</sub>D<sub>3</sub> catabolism over 24 h. A further indication of CYP24A1 inhibition by <b>VD1-6</b> was the reduced accumulation of the 24,25(OH)D<sub>3</sub>, the first metabolite of 25(OH)D catabolism by CYP24A1. Our findings suggest the potent CYP24A1 inhibitory properties of <b>VD1-6</b> and its potential for testing as an alternative therapeutic candidate for treating SHPT.https://www.mdpi.com/2218-273X/12/7/960vitamin D<sub>3</sub>CYP24A1in silico dockingcatabolism inhibitionHEK293T |
| spellingShingle | Ali K. Alshabrawy Yingjie Cui Cyan Sylvester Dongqing Yang Emilio S. Petito Kate R. Barratt Rebecca K. Sawyer Jessica K. Heatlie Ruhi Polara Matthew J. Sykes Gerald J. Atkins Shane M. Hickey Michael D. Wiese Andrea M. Stringer Zhaopeng Liu Paul H. Anderson Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding Biomolecules vitamin D<sub>3</sub> CYP24A1 in silico docking catabolism inhibition HEK293T |
| title | Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding |
| title_full | Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding |
| title_fullStr | Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding |
| title_full_unstemmed | Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding |
| title_short | Therapeutic Potential of a Novel Vitamin D<sub>3</sub> Oxime Analogue, VD1-6, with CYP24A1 Enzyme Inhibitory Activity and Negligible Vitamin D Receptor Binding |
| title_sort | therapeutic potential of a novel vitamin d sub 3 sub oxime analogue vd1 6 with cyp24a1 enzyme inhibitory activity and negligible vitamin d receptor binding |
| topic | vitamin D<sub>3</sub> CYP24A1 in silico docking catabolism inhibition HEK293T |
| url | https://www.mdpi.com/2218-273X/12/7/960 |
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