An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation
Biliverdin IXβ reductase (BLVRB) has emerged as a promising therapeutic target for thrombocytopenia due to its involvement in reactive oxygen species (ROS) mechanisms. During the pursuit of inhibitors targeting BLVRB, olsalazine (OSA) became apparent as one of the most potent candidates. However, th...
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| author | Hoe-Myung Jung Jung-Hye Ha Mark Vincent C. dela Cerna Joseph A. Burlison Joonhyeok Choi Bo-Ram Kim Jeong Kyu Bang Kyoung-Seok Ryu Donghan Lee |
| author_facet | Hoe-Myung Jung Jung-Hye Ha Mark Vincent C. dela Cerna Joseph A. Burlison Joonhyeok Choi Bo-Ram Kim Jeong Kyu Bang Kyoung-Seok Ryu Donghan Lee |
| author_sort | Hoe-Myung Jung |
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| description | Biliverdin IXβ reductase (BLVRB) has emerged as a promising therapeutic target for thrombocytopenia due to its involvement in reactive oxygen species (ROS) mechanisms. During the pursuit of inhibitors targeting BLVRB, olsalazine (OSA) became apparent as one of the most potent candidates. However, the direct application of OSA as a BLVRB inhibitor faces challenges, as it is prone to degradation into 5-aminosalicylic acid through cleavage of the diazenyl bond by abundant azoreductase (AzoR) enzymes in gut microbiota and eukaryotic cells. To overcome this obstacle, we devised olsalkene (OSK), an inhibitor where the diazenyl bond in OSA has been substituted with an alkene bond. OSK not only matches the efficacy of OSA but also demonstrates improved stability against degradation by AzoR, presenting a promising solution to this limitation. Furthermore, we have found that both OSK and OSA inhibit BLVRB, regardless of the presence of nicotinamide adenine dinucleotide phosphate, unlike other known inhibitors. This discovery opens new avenues for investigating the roles of BLVRB in blood disorders, including thrombocytopenia. |
| format | Article |
| id | doaj-art-d0c6a89005ea45e5a924a5479f140149 |
| institution | OA Journals |
| issn | 1999-4923 |
| language | English |
| publishDate | 2024-08-01 |
| publisher | MDPI AG |
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| series | Pharmaceutics |
| spelling | doaj-art-d0c6a89005ea45e5a924a5479f1401492025-08-20T01:55:46ZengMDPI AGPharmaceutics1999-49232024-08-01169114810.3390/pharmaceutics16091148An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular DegradationHoe-Myung Jung0Jung-Hye Ha1Mark Vincent C. dela Cerna2Joseph A. Burlison3Joonhyeok Choi4Bo-Ram Kim5Jeong Kyu Bang6Kyoung-Seok Ryu7Donghan Lee8Korea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si 28119, Republic of KoreaNew Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), 80 Cheombok-ro, Dong-gu, Daegu 41061, Republic of KoreaDepartment of Biochemistry, Chemistry and Physics, Georgia Southern University, 11935 Abercorn Street, Savannah, GA 31419, USADepartment of Medicine, James Graham Brown Cancer Center, University of Louisville, 505 S. Hancock St., Louisville, KY 40202, USAKorea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si 28119, Republic of KoreaKorea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si 28119, Republic of KoreaKorea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si 28119, Republic of KoreaKorea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si 28119, Republic of KoreaKorea Basic Science Institute, 162 Yeongudanji-Ro, Ochang-Eup, Cheongju-Si 28119, Republic of KoreaBiliverdin IXβ reductase (BLVRB) has emerged as a promising therapeutic target for thrombocytopenia due to its involvement in reactive oxygen species (ROS) mechanisms. During the pursuit of inhibitors targeting BLVRB, olsalazine (OSA) became apparent as one of the most potent candidates. However, the direct application of OSA as a BLVRB inhibitor faces challenges, as it is prone to degradation into 5-aminosalicylic acid through cleavage of the diazenyl bond by abundant azoreductase (AzoR) enzymes in gut microbiota and eukaryotic cells. To overcome this obstacle, we devised olsalkene (OSK), an inhibitor where the diazenyl bond in OSA has been substituted with an alkene bond. OSK not only matches the efficacy of OSA but also demonstrates improved stability against degradation by AzoR, presenting a promising solution to this limitation. Furthermore, we have found that both OSK and OSA inhibit BLVRB, regardless of the presence of nicotinamide adenine dinucleotide phosphate, unlike other known inhibitors. This discovery opens new avenues for investigating the roles of BLVRB in blood disorders, including thrombocytopenia.https://www.mdpi.com/1999-4923/16/9/1148biliverdin IXβ reductase-inhibitor complex structureazoreductase-resistant inhibitorthrombocytopeniaNMR spectroscopyX-ray crystallography |
| spellingShingle | Hoe-Myung Jung Jung-Hye Ha Mark Vincent C. dela Cerna Joseph A. Burlison Joonhyeok Choi Bo-Ram Kim Jeong Kyu Bang Kyoung-Seok Ryu Donghan Lee An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation Pharmaceutics biliverdin IXβ reductase-inhibitor complex structure azoreductase-resistant inhibitor thrombocytopenia NMR spectroscopy X-ray crystallography |
| title | An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation |
| title_full | An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation |
| title_fullStr | An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation |
| title_full_unstemmed | An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation |
| title_short | An Innovative Inhibitor with a New Chemical Moiety Aimed at Biliverdin IXβ Reductase for Thrombocytopenia and Resilient against Cellular Degradation |
| title_sort | innovative inhibitor with a new chemical moiety aimed at biliverdin ixβ reductase for thrombocytopenia and resilient against cellular degradation |
| topic | biliverdin IXβ reductase-inhibitor complex structure azoreductase-resistant inhibitor thrombocytopenia NMR spectroscopy X-ray crystallography |
| url | https://www.mdpi.com/1999-4923/16/9/1148 |
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