Hemoglobin Variants as Targets for Stabilizing Drugs
Hemoglobin is an oxygen-transport protein in red blood cells that interacts with multiple ligands, e.g., oxygen, carbon dioxide, carbon monoxide, and nitric oxide. Genetic variations in hemoglobin chains, such as those underlying sickle cell disease and thalassemias, present substantial clinical cha...
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MDPI AG
2025-01-01
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| Series: | Molecules |
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| Online Access: | https://www.mdpi.com/1420-3049/30/2/385 |
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| author | Miroslava Žoldáková Michal Novotný Krishna P. Khakurel Gabriel Žoldák |
| author_facet | Miroslava Žoldáková Michal Novotný Krishna P. Khakurel Gabriel Žoldák |
| author_sort | Miroslava Žoldáková |
| collection | DOAJ |
| description | Hemoglobin is an oxygen-transport protein in red blood cells that interacts with multiple ligands, e.g., oxygen, carbon dioxide, carbon monoxide, and nitric oxide. Genetic variations in hemoglobin chains, such as those underlying sickle cell disease and thalassemias, present substantial clinical challenges. Here, we review the progress in research, including the use of allosteric modulators, pharmacological chaperones, and antioxidant treatments, which has begun to improve hemoglobin stability and oxygen affinity. According to UniProt (as of 7 August 2024), 819 variants of the α-hemoglobin subunit and 771 variants of the β-hemoglobin subunit have been documented, with over 116 classified as unstable. These data demonstrate the urgent need to develop variant-specific stabilizing options. Beyond small-molecule drugs/binders, novel protein-based strategies—such as engineered hemoglobin-binding proteins (including falcilysin, llama-derived nanobodies, and α-hemoglobin-stabilizing proteins)—offer promising new options. As our understanding of hemoglobin’s structural and functional diversity grows, so does the potential for genotype-driven approaches. Continued research into hemoglobin stabilization and ligand-binding modification may yield more precise, effective treatments and pave the way toward effective strategies for hemoglobinopathies. |
| format | Article |
| id | doaj-art-5b646e3c97aa43749ddf265d24921308 |
| institution | Kabale University |
| issn | 1420-3049 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Molecules |
| spelling | doaj-art-5b646e3c97aa43749ddf265d249213082025-01-24T13:43:51ZengMDPI AGMolecules1420-30492025-01-0130238510.3390/molecules30020385Hemoglobin Variants as Targets for Stabilizing DrugsMiroslava Žoldáková0Michal Novotný1Krishna P. Khakurel2Gabriel Žoldák3Faculty of Science, Pavol Jozef Šafárik University in Košice, Park Angelinum 19, 040 01 Košice, SlovakiaAURORA R&D s.r.o., Mojmírova 12, 040 01 Košice, SlovakiaExtreme Light Infrastructure ERIC, Za Radnici 835, 25241 Dolni Brezany, Czech RepublicFaculty of Science, Pavol Jozef Šafárik University in Košice, Park Angelinum 19, 040 01 Košice, SlovakiaHemoglobin is an oxygen-transport protein in red blood cells that interacts with multiple ligands, e.g., oxygen, carbon dioxide, carbon monoxide, and nitric oxide. Genetic variations in hemoglobin chains, such as those underlying sickle cell disease and thalassemias, present substantial clinical challenges. Here, we review the progress in research, including the use of allosteric modulators, pharmacological chaperones, and antioxidant treatments, which has begun to improve hemoglobin stability and oxygen affinity. According to UniProt (as of 7 August 2024), 819 variants of the α-hemoglobin subunit and 771 variants of the β-hemoglobin subunit have been documented, with over 116 classified as unstable. These data demonstrate the urgent need to develop variant-specific stabilizing options. Beyond small-molecule drugs/binders, novel protein-based strategies—such as engineered hemoglobin-binding proteins (including falcilysin, llama-derived nanobodies, and α-hemoglobin-stabilizing proteins)—offer promising new options. As our understanding of hemoglobin’s structural and functional diversity grows, so does the potential for genotype-driven approaches. Continued research into hemoglobin stabilization and ligand-binding modification may yield more precise, effective treatments and pave the way toward effective strategies for hemoglobinopathies.https://www.mdpi.com/1420-3049/30/2/385hemoglobin (Hb)oxygen affinityallosteric regulationBohr effect2,3-bisphosphoglycerate (2,3-BPG)genetic variants |
| spellingShingle | Miroslava Žoldáková Michal Novotný Krishna P. Khakurel Gabriel Žoldák Hemoglobin Variants as Targets for Stabilizing Drugs Molecules hemoglobin (Hb) oxygen affinity allosteric regulation Bohr effect 2,3-bisphosphoglycerate (2,3-BPG) genetic variants |
| title | Hemoglobin Variants as Targets for Stabilizing Drugs |
| title_full | Hemoglobin Variants as Targets for Stabilizing Drugs |
| title_fullStr | Hemoglobin Variants as Targets for Stabilizing Drugs |
| title_full_unstemmed | Hemoglobin Variants as Targets for Stabilizing Drugs |
| title_short | Hemoglobin Variants as Targets for Stabilizing Drugs |
| title_sort | hemoglobin variants as targets for stabilizing drugs |
| topic | hemoglobin (Hb) oxygen affinity allosteric regulation Bohr effect 2,3-bisphosphoglycerate (2,3-BPG) genetic variants |
| url | https://www.mdpi.com/1420-3049/30/2/385 |
| work_keys_str_mv | AT miroslavazoldakova hemoglobinvariantsastargetsforstabilizingdrugs AT michalnovotny hemoglobinvariantsastargetsforstabilizingdrugs AT krishnapkhakurel hemoglobinvariantsastargetsforstabilizingdrugs AT gabrielzoldak hemoglobinvariantsastargetsforstabilizingdrugs |