New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?
Esther OderMartin K SafoOsheiza AbdulmalikGregory J KatoPublished in: British journal of haematology (2016)
The hallmark of sickle cell disease is the polymerization of sickle haemoglobin due to a point mutation in the β-globin gene (HBB). Under low oxygen saturation, sickle haemoglobin assumes the tense (T-state) deoxygenated conformation that can form polymers, leading to rigid erythrocytes with impaired blood vessel transit, compounded or initiated by adhesion of erythrocytes to endothelium, neutrophils and platelets. This process results in vessel occlusion and ischaemia, with consequent acute pain, chronic organ damage, morbidity and mortality. Pharmacological agents that stabilize the higher oxygen affinity relaxed state (R-state) and/or destabilize the lower oxygen affinity T-state of haemoglobin have the potential to delay the sickling of circulating red cells by slowing polymerization kinetics. Relevant classes of agents include aromatic aldehydes, thiol derivatives, isothiocyanates and acyl salicylates derivatives. The aromatic aldehyde, 5-hydroxymethylfurfural (5-HMF) increases oxygen affinity of sickle haemoglobin and reduces hypoxia-induced sickling in vitro and protects sickle cell mice from effects of hypoxia. It has completed pre-clinical testing and has entered clinical trials as treatment for sickle cell disease. A related molecule, GBT440, has shown R-state stabilization and increased oxygen affinity in preclinical testing. Allosteric modifiers of haemoglobin as direct anti-sickling agents target the fundamental pathophysiological mechanism of sickle cell disease.
Keyphrases
- sickle cell disease
- clinical trial
- drug induced
- oxidative stress
- small molecule
- induced apoptosis
- nitric oxide
- liver failure
- stem cells
- pain management
- type diabetes
- genome wide
- endothelial cells
- neuropathic pain
- escherichia coli
- metabolic syndrome
- adipose tissue
- bone marrow
- randomized controlled trial
- spinal cord
- spinal cord injury
- cell death
- mass spectrometry
- dna methylation
- climate change
- signaling pathway
- combination therapy
- human health
- cystic fibrosis
- cell migration
- red blood cell
- smoking cessation