New developments in anti-sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin in vivo?
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.
School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA.
Esther
E
Oder
Department of Medicinal Chemistry, Institute for Structural Biology, Drug Discovery and Development, School of Pharmacy, Virginia Commonwealth University, Richmond, VA, USA.
Martin K
MK
Safo
Division of Hematology, The Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Osheiza
O
Abdulmalik
Department of Medicine, Division of Hematology-Oncology and the Heart, Lung, Blood and Vascular Medicine Institute, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. katogj@upmc.edu.
Gregory J
0000-0003-4465-3217
GJ
Kato
D000494:Allosteric Regulation / Q000187:drug effects; D000755:Anemia, Sickle Cell / Q000097:blood* / Q000188:drug therapy*; D000818:Animals; D000986:Antisickling Agents / Q000494:pharmacology / Q000627:therapeutic use*; D055808:Drug Discovery; D004913:Erythrocytes, Abnormal / Q000378:metabolism; D006451:Hemoglobin, Sickle / Q000737:chemistry / Q000378:metabolism; D006454:Hemoglobins / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D010100:Oxygen / Q000378:metabolism; D066329:Protein Aggregates / Q000187:drug effects; D066263:Protein Aggregation, Pathological / Q000188:drug therapy
D000986:Antisickling Agents; D006451:Hemoglobin, Sickle; D006454:Hemoglobins; D066329:Protein Aggregates; D010100:Oxygen
5-hydroxymethylfurfural; GBT440; TD-1; anti-sickling; haemoglobin allosteric effectors; sickle cell; vanillin