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Abstract
Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal6 that changes normal Hb (HbA) into sickle Hb (HbS). Under hypoxia, HbS polymerizes into rigid fibers, causing red blood cells (RBCs) to sickle; leading to numerous adverse pathological effects. The RBC sickling is made worse by the low oxygen (O2) affinity of HbS, due to elevated intra-RBC concentrations of the natural Hb effector, 2,3-diphosphoglycerate. This has prompted the development of Hb modifiers, such as aromatic aldehydes, with the intent of increasing Hb affinity for O2 with subsequent prevention of RBC sickling. One such molecule, Voxelotor was recently approved by U.S. FDA to treat SCD. Here we report results of a novel aromatic aldehyde, VZHE-039, that mimics both the O2-dependent and O2-independent antisickling properties of fetal hemoglobin. The latter mechanism of action—as elucidated through crystallographic and biological studies—is likely due to disruption of key intermolecular contacts necessary for stable HbS polymer formation. This dual antisickling mechanism, in addition to VZHE-039 metabolic stability, has translated into significantly enhanced and sustained pharmacologic activities. Finally, VZHE-039 showed no significant inhibition of several CYPs, demonstrated efficient RBC partitioning and high membrane permeability, and is not an efflux transporter (P-gp) substrate.
Highlights
Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal[6] that changes normal Hb (HbA) into sickle Hb (HbS)
Structure-based approach to sequentially improve the inherent design of aromatic aldehyde-containing vanillin analogs[30,31,32,33,34,35,36,37,38,40,41], we have identified a novel aromatic aldehyde, VZHE-039, that shows improved PK/PD properties but demonstrates unique antisickling properties
We have previously demonstrated through structural studies, that two molecules of the naturally occurring antisickling aromatic aldehydes, vanillin or 5-HMF preferentially bind at the α-cleft of liganded Hb in the R2-state conformation, form Schiff-base interactions with αVal[1] amines to increase the protein affinity for oxygen, reduce hypoxia-induced HbS polymerization and red blood cells (RBCs) sickling[34]
Summary
Sickle cell disease (SCD) results from a hemoglobin (Hb) mutation βGlu6 → βVal[6] that changes normal Hb (HbA) into sickle Hb (HbS). The clinical efficacy of Voxelotor for SCD treatment is based on increased Hb levels and reduced hemolysis in p atients[25] These surrogate endpoints are not long-term clinical outcomes, the phase III trial provided additional encouraging evidence that aromatic aldehydes may have disease-modifying potential that can mitigate adverse disease effects of RBC sickling. Vanillin and 5-HMF have been studied for their potential to treat S CD30,34,38,39, but weak pharmacodynamic (PD) and/or poor pharmacokinetic (PK) properties, in part due to extensive oxidative metabolism of the aldehyde primarily by aldehyde dehydrogenase (ALDH) in the RBCs (target site), and liver[46,47,48], have hampered their development into viable SCD therapeutics These compounds serve as highly valuable, effective, and non-toxic design scaffolds, as exemplified by the successful development of V oxelotor[25,26,27,28]
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