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

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.

Keywords: 5-hydroxymethylfurfural; GBT440; TD-1; anti-sickling; haemoglobin allosteric effectors; sickle cell; vanillin.

Figure 1

Chemical structures of aromatic aldehydes and their complexes with liganded haemoglobin. (A) Structures of aromatic aldehydes. (B) Binding of 5-hydroxymethylfurfural (5-HMF; orange) in a symmetry-related fashion at the α-cleft of liganded Hb, and through a series of inter-subunit hydrogen-bond and/or hydrophobic interactions, stabilize the R-state conformation. (C) Binding of a pyridyl derivative of vanillin, INN-312 (orange) in a symmetry-related fashion at the α-cleft of liganded Hb, which leads to stabilization of the relaxed state conformation. Additionally, the pyridine moiety of INN-312 makes hydrophobic interactions with the F-helix, perturbing the inter-strand polymer contact involving Asn78, and contributing to the anti-sickling activity of the compound.

Figure 1

Chemical structures of aromatic aldehydes and their complexes with liganded haemoglobin. (A) Structures of aromatic aldehydes. (B) Binding of 5-hydroxymethylfurfural (5-HMF; orange) in a symmetry-related fashion at the α-cleft of liganded Hb, and through a series of inter-subunit hydrogen-bond and/or hydrophobic interactions, stabilize the R-state conformation. (C) Binding of a pyridyl derivative of vanillin, INN-312 (orange) in a symmetry-related fashion at the α-cleft of liganded Hb, which leads to stabilization of the relaxed state conformation. Additionally, the pyridine moiety of INN-312 makes hydrophobic interactions with the F-helix, perturbing the inter-strand polymer contact involving Asn78, and contributing to the anti-sickling activity of the compound.

Figure 1

Chemical structures of aromatic aldehydes and their complexes with liganded haemoglobin. (A) Structures of aromatic aldehydes. (B) Binding of 5-hydroxymethylfurfural (5-HMF; orange) in a symmetry-related fashion at the α-cleft of liganded Hb, and through a series of inter-subunit hydrogen-bond and/or hydrophobic interactions, stabilize the R-state conformation. (C) Binding of a pyridyl derivative of vanillin, INN-312 (orange) in a symmetry-related fashion at the α-cleft of liganded Hb, which leads to stabilization of the relaxed state conformation. Additionally, the pyridine moiety of INN-312 makes hydrophobic interactions with the F-helix, perturbing the inter-strand polymer contact involving Asn78, and contributing to the anti-sickling activity of the compound.