New developments in anti‐sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?

Abstract

Summary 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.

A clinically meaningful fetal hemoglobin threshold for children with sickle cell anemia during hydroxyurea therapy

“…They underscore the need for novel therapies to augment the effect of hydroxyurea in increasing HbF% to treat acute vaso-occlusive complications 41 and novel anti-sickling agents 42 .…”

Targeting βCys93 in hemoglobin S with an antisickling agent possessing dual allosteric and antioxidant effects

“…5-HMF binds outside the “hotspot” area that contains βCys93, specifically to the N-terminal valine residues of HbS α-globin chains, forming a Schiff-base adduct which likely stabilizes the R- state (34). We have found that this compound provided no oxidative protection under similar oxidative stress conditions used in this study (unpublished data).…”

Treating sickle cell disease by targeting HbS polymerization

“…This agent is an aldehyde that forms a reversible Schiff base linkage primarily with the N-terminal amino group of a-globin resulting in a dose-dependent increase in oxygen affinity. [102][103][104] A significant concern with aldehyde drugs is their potential to covalently modify other cellular and plasma proteins. More recently, a polyaromatic aldehyde, GBT440, has been developed that also binds via a Schiff base to the a-globin N terminus with enhancement of oxygen affinity similar to Aes-103, but with higher specificity and at much lower concentrations.…”