FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors
Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase repor...
Saved in:
| Main Authors: | , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2012-01-01
|
| Series: | Anemia |
| Online Access: | http://dx.doi.org/10.1155/2012/428137 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1832567112725430272 |
|---|---|
| author | Levi Makala Salvatore Di Maro Tzu-Fang Lou Sharanya Sivanand Jung-Mo Ahn Betty S. Pace |
| author_facet | Levi Makala Salvatore Di Maro Tzu-Fang Lou Sharanya Sivanand Jung-Mo Ahn Betty S. Pace |
| author_sort | Levi Makala |
| collection | DOAJ |
| description | Fetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD. |
| format | Article |
| id | doaj-art-9052f7f8b5c04daa927ae5a99199454b |
| institution | Kabale University |
| issn | 2090-1267 2090-1275 |
| language | English |
| publishDate | 2012-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Anemia |
| spelling | doaj-art-9052f7f8b5c04daa927ae5a99199454b2025-02-03T01:02:19ZengWileyAnemia2090-12672090-12752012-01-01201210.1155/2012/428137428137FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid ProgenitorsLevi Makala0Salvatore Di Maro1Tzu-Fang Lou2Sharanya Sivanand3Jung-Mo Ahn4Betty S. Pace5Department of Pediatrics, Georgia Health Sciences University, Augusta, GA 30912, USADepartment of Chemistry, University of Texas at Dallas, Richardson, TX 75083, USADepartment of Molecular and Cell Biology, University of Texas at Dallas, TX 75080, USADepartment of Developmental Biology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USADepartment of Chemistry, University of Texas at Dallas, Richardson, TX 75083, USADepartment of Pediatrics, Georgia Health Sciences University, Augusta, GA 30912, USAFetal hemoglobin (HbF) improves the clinical severity of sickle cell disease (SCD), therefore, research to identify HbF-inducing agents for treatment purposes is desirable. The focus of our study is to investigate the ability of FK228 analogues to induce HbF using a novel KU812 dual-luciferase reporter system. Molecular modeling studies showed that the structure of twenty FK228 analogues with isosteric substitutions did not disturb the global structure of the molecule. Using the dual-luciferase system, a subgroup of FK228 analogues was shown to be inducers of HbF at nanomolar concentrations. To determine the physiological relevance of these compounds, studies in primary erythroid progenitors confirmed that JMA26 and JMA33 activated HbF synthesis at levels comparable to FK228 with low cellular toxicity. These data support our lead compounds as potential therapeutic agents for further development in the treatment of SCD.http://dx.doi.org/10.1155/2012/428137 |
| spellingShingle | Levi Makala Salvatore Di Maro Tzu-Fang Lou Sharanya Sivanand Jung-Mo Ahn Betty S. Pace FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors Anemia |
| title | FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors |
| title_full | FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors |
| title_fullStr | FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors |
| title_full_unstemmed | FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors |
| title_short | FK228 Analogues Induce Fetal Hemoglobin in Human Erythroid Progenitors |
| title_sort | fk228 analogues induce fetal hemoglobin in human erythroid progenitors |
| url | http://dx.doi.org/10.1155/2012/428137 |
| work_keys_str_mv | AT levimakala fk228analoguesinducefetalhemoglobininhumanerythroidprogenitors AT salvatoredimaro fk228analoguesinducefetalhemoglobininhumanerythroidprogenitors AT tzufanglou fk228analoguesinducefetalhemoglobininhumanerythroidprogenitors AT sharanyasivanand fk228analoguesinducefetalhemoglobininhumanerythroidprogenitors AT jungmoahn fk228analoguesinducefetalhemoglobininhumanerythroidprogenitors AT bettyspace fk228analoguesinducefetalhemoglobininhumanerythroidprogenitors |