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Under low oxygen saturation, sickle haemoglobin assumes the tense (T\u2010state) 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\u2010state) and\/or destabilize the lower oxygen affinity T\u2010state 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\u2010hydroxymethylfurfural (5\u2010<jats:styled-content style=\"fixed-case\">HMF<\/jats:styled-content>) increases oxygen affinity of sickle haemoglobin and reduces hypoxia\u2010induced sickling <jats:italic>in\u00a0vitro<\/jats:italic> and protects sickle cell mice from effects of hypoxia. It has completed pre\u2010clinical testing and has entered clinical trials as treatment for sickle cell disease. A related molecule, <jats:styled-content style=\"fixed-case\">GBT<\/jats:styled-content>440, has shown R\u2010state stabilization and increased oxygen affinity in preclinical testing. Allosteric modifiers of\u00a0haemoglobin as direct anti\u2010sickling agents target the fundamental pathophysiological mechanism of sickle cell disease.<\/jats:p>","DOI":"10.1111\/bjh.14264","type":"journal-article","created":{"date-parts":[[2016,9,8]],"date-time":"2016-09-08T06:13:31Z","timestamp":1473315211000},"page":"24-30","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":71,"title":["New developments in anti\u2010sickling agents: can drugs directly prevent the polymerization of sickle haemoglobin <i>in\u00a0vivo<\/i>?"],"prefix":"10.1111","volume":"175","author":[{"given":"Esther","family":"Oder","sequence":"first","affiliation":[{"name":"School of Pharmacy University of Pittsburgh Pittsburgh PA USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martin K.","family":"Safo","sequence":"additional","affiliation":[{"name":"Department of Medicinal Chemistry Institute for Structural Biology Drug Discovery and 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