Challenges of the allosteric regulation of hemoglobin by interaction with Cys93 of the β chain for the treatment of sickle cell disease

Abstract Voxelotor exerts its regulatory effect on the affinity of hemoglobin for oxygen through an allosteric mechanism involving binding of the drug to the α-chain of hemoglobin. Cystein 93 of the β-chain of hemoglobin is an additional allosteric regulatory site of Hb affinity for oxygen that has been investigated for several decades as a potential target for the treatment of sickle cell disease. This review covers research, in vitro and in preclinical models, on several thiol-reactive molecules such as iodoacetamide, N-ethylmaleimide, 1-bromoacetyl-3,3-dinitroazetidine, isothiocyanate derivatives, thimerosal, glutathione, triazole disulfide, and allyl disulfide, which bind to β-Cysteine 93. Although these compounds were effectively employed to demonstrate that β-Cysteine 93 is an allosteric regulator of hemoglobin function, none of them have yet provided the safety and preclinical data to allow the initiation of clinical trials for the treatment of SCD. Such an opportunity may be provided by repositioning dalcetrapib, an orally available and safe thiol derivative currently in Phase 3 clinical trials for the prevention of cardiovascular events: dalcetrapib has been shown to reduce the incidence of cardiovascular events in patients with the AA genotype of the Adenylyl Cyclase 9, rs1967309 variant, which is prevalent in people of African descent. Recently, dalcetrapib was also observed to bind to Cysteine 93 of the β-chain of hemoglobin, leading to a reduction in hemoglobin S polymerization and alterations in hemoglobin interaction with oxygen. Dalcetrapib could therefore be a therapeutic that limits red blood cell sickling in SCD patients, thus mitigating the associated complications. Nonetheless, clinical trials on dalcetrapib in this population are currently lacking.