New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?
Year: 2016
Type: review
Abstract: 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.
Source: British Journal of Haematology
DOI: 10.1111/bjh.14264
Language: English
Subfield: Genetics (clinical)
Field: Medicine
Domain: Health Sciences
Open Access status: green
Awards: Development of Antisickling Drug Aes-103 in Patients with Sickle Cell Disease, Structure and Function of Stability-Enhanced Beta-Globin mRNAs, Characterizing mechanisms of sickle cell crisis via dynamic optical assay, Hemoglobin Modifiers for Sickle Cell Disease Therapy, SCN5A gene and prolonged QT in sickle cell disease, CHANGES IN THE RBC PROTEOME DURING HEALTH AND DISEASE, Preclinical Innovation, Massey Cancer Center - Cancer Center Support Grant
OpenAlex ID: W2510810968