Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

Safo, Martin K.; Kato, Gregory J.

doi:10.1016/j.hoc.2013.11.001

Cited by 67 publications

(104 citation statements)

References 95 publications

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“…There are only two compounds currently in clinical trials for the treatment of sickle cell disease that act by inhibiting polymerization. One is 5-hydroxymethyl-2-furfural (called AES-103; ClinicalTrials.gov identifier NCT019879080) (39). The other is 2-hydroxy-6((2-(1-isopropyl-1H-pyrazol-5-yl)pyridin-3-yl)methoxy)benzaldehyde) (called GBT440; ClinicalTrials.gov identifier NCT02285088; ref.…”

Section: Resultsmentioning

confidence: 99%

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Henry

Hofrichter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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Although it has been known for more than 60 years that the cause of sickle cell disease is polymerization of a hemoglobin mutant, hydroxyurea is the only drug approved for treatment by the US Food and Drug Administration. This drug, however, is only partially successful, and the discovery of additional drugs that inhibit fiber formation has been hampered by the lack of a sensitive and quantitative cellular assay. Here, we describe such a method in a 96-well plate format that is based on laser-induced polymerization in sickle trait cells and robust, automated image analysis to detect the precise time at which fibers distort ("sickle") the cells. With this kinetic method, we show that small increases in cell volume to reduce the hemoglobin concentration can result in therapeutic increases in the delay time prior to fiber formation. We also show that, of the two drugs (AES103 and GBT440) in clinical trials that inhibit polymerization by increasing oxygen affinity, one of them (GBT440) also inhibits sickling in the absence of oxygen by two additional mechanisms.sickle cell | drugs | hemoglobin S | treatment | screening assay

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Section: Resultsmentioning

confidence: 99%

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Henry

Hofrichter

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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“…7,18,21,22 5-hydoxymethyl-2-furfural (5-HMF, aka Aes-103) is one such left-shifting allosteric effector that binds to both R-state and T-state Hb, and shown to prevent Hb S polymerization and erythrocyte sickling. 10,17,18 5-HMF is currently in phase II clinical studies for the treatment of SCD. A potential problem for the use of aromatic aldehydes as SCD therapy is their poor pharmacokinetic properties (due to metabolic instability of the aldehyde function as a result of aldehyde dehydrogenase metabolism) which may necessitate large amounts and frequent dosing to reach therapeutic level.…”

Section: Introductionmentioning

confidence: 99%

“…A potential problem for the use of aromatic aldehydes as SCD therapy is their poor pharmacokinetic properties (due to metabolic instability of the aldehyde function as a result of aldehyde dehydrogenase metabolism) which may necessitate large amounts and frequent dosing to reach therapeutic level. 10 This has prompted several studies to find alternate covalent modifiers of Hb, such as isothiocynates and thiols to treat the disease. 23,24 …”

Section: Introductionmentioning

confidence: 99%

Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

et al. 2015

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Aromatic aldehydes and ethacrynic acid (ECA) exhibit antipolymerization properties that are beneficial for sickle cell disease therapy. Based on ECA pharmacophore and its atomic interaction with hemoglobin, we designed and synthesized several compounds--designated as KAUS (imidazolylacryloyl derivatives)--that we hypothesized would bind covalently to βCys93 of hemoglobin and inhibit sickling. The compounds surprisingly showed weak allosteric and antisickling properties. X-ray studies of hemoglobin in complex with representative KAUS compounds revealed an unanticipated mode of Michael addition reaction between the β-unsaturated carbon and the N-terminal αVal1 nitrogen at the α-cleft of hemoglobin, with no observable interaction with βCys93. Interestingly, the compounds exhibited almost no reactivity with the free amino acids, L-Val, L-His and L-Lys, however showed some reactivity with both glutathione and L-Cys. Our findings provide a molecular level explanation to the compounds biological activities and an important framework for targeted modifications that would yield novel potent antisickling agents.

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“…The pharmacologic effect of these compounds primarily involves formation of a Schiff-base interaction between the aldehyde moiety of the compound and the N-terminal amine of α Val1 of the liganded Hb and, along with other protein interactions, stabilizes the R-state Hb in the R2 conformation, thus increasing Hb affinity for oxygen. 6,11–15 Consistently, the synthetic derivatives, such as Tucaresol and GBT-440, with apparent increased protein interactions have demonstrated both enhanced potency and improved pharmacokinetic properties than the parent vanillin. 13,16,17 Unlike the above-mentioned aromatic aldehydes, there are other classes of aromatic aldehydes that bind Hb and preferentially stabilize the T-state relative to the R-state resulting in a decrease in Hb affinity for oxygen.…”

Section: Introductionmentioning

confidence: 93%

“…6,11,12 Consequently, several candidates, such as vanillin and its derivatives (INN compounds, Tucaresol, and Valeresol), 5-HMF, and most recently, GBT-440 have been established to increase the oxygen affinity of Hb S to counter polymerization, thereby providing a potential therapeutic intervention for SCD. 6,11–19 Vanillin, Tucaresol, Valeresol, and 5-HMF have undergone phase I and/or II studies, 6,16,20–24 while GBT-440 is currently undergoing a phase III clinical studies for the treatment of SCD (clinicaltrials.gov, NCT03036813), suggesting a viable route to treat this disease with aromatic aldehydes. The pharmacologic effect of these compounds primarily involves formation of a Schiff-base interaction between the aldehyde moiety of the compound and the N-terminal amine of α Val1 of the liganded Hb and, along with other protein interactions, stabilizes the R-state Hb in the R2 conformation, thus increasing Hb affinity for oxygen.…”

Section: Introductionmentioning

confidence: 99%

Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease

Xu¹,

Pagare²,

Ghatge³

et al. 2017

Mol. Pharmaceutics

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Candidate drugs to counter intracellular polymerization of deoxygenated sickle hemoglobin (Hb S) continue to represent a promising approach to mitigating the primary cause of the pathophysiology associated with sickle cell disease (SCD). One such compound is the naturally occurring antisickling agent, 5-hydroxymethyl-2-furfural (5-HMF), which has been studied in the clinic for the treatment of SCD. As part of our efforts to develop novel efficacious drugs with improved pharmacologic properties, we structurally modified 5-HMF into 12 ether and ester derivatives. The choice of 5-HMF as a pharmacophore was influenced by a combination of its demonstrated attractive hemoglobin modifying and antisickling properties, well-known safety profiles, and its reported nontoxic major metabolites. The derivatives were investigated for their time- and/or dose-dependent effects on important antisickling parameters, such as modification of hemoglobin, corresponding changes in oxygen affinity, and inhibition of red blood cell sickling. The novel test compounds bound and modified Hb and concomitantly increased the protein affinity for oxygen. Five of the derivatives exhibited 1.5- to 4.0-fold higher antisickling effects than 5-HMF. The binding mode of the compounds with Hb was confirmed by X-ray crystallography and, in part, helps explain their observed biochemical properties. Our findings, in addition to the potential therapeutic application, provide valuable insights and potential guidance for further modifications of these (and similar) compounds to enhance their pharmacologic properties.

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Therapeutic Strategies to Alter the Oxygen Affinity of Sickle Hemoglobin

Cited by 67 publications

References 95 publications

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Kinetic assay shows that increasing red cell volume could be a treatment for sickle cell disease

Identification of a novel class of covalent modifiers of hemoglobin as potential antisickling agents

Design, Synthesis, and Biological Evaluation of Ester and Ether Derivatives of Antisickling Agent 5-HMF for the Treatment of Sickle Cell Disease

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