Requirements for therapeutic inhibition of sickle haemoglobin gelation

Sunshine, Helen R.; Hofrichter, James; Eaton, William A.

doi:10.1038/275238a0

Cited by 134 publications

(90 citation statements)

References 23 publications

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“…In vitro studies have shown that both fetal hemoglobin (HbF) (α 2 γ 2 ) tetramers and (α 2 β S γ) tetramers inhibit HbS polymerization. 7 Because increased levels of HbF lessen the severity of symptoms and increase the life expectancy of patients with SCD, therapeutic approaches to increase HbF levels would be highly desirable. 8,9 While many drugs increase HbF in cultured erythroid cells, only a few have been shown to increase HbF in vivo.…”

Section: Introductionmentioning

confidence: 99%

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

et al. 2016

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Section: Introductionmentioning

confidence: 99%

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

et al. 2016

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“…Abbreviations used in this paper: DIOA, ([dihydroindenyl]-oxy)alkanoic acid; DS, density score; HbF, fetal hemoglobin; MCHC, mean corpuscular hemoglobin concentration; RBC, red blood cells; TfR, transferrin receptor; WBC, white blood cells. logic, and membrane abnormalities (1), and their higher intracellular hemogJobin concentration greatly favors the formation of sickle hemoglobin (HbS) polymer (2,3). Included in this population are cells which became abnormally dense either before or soon after release from the bone marrow, as indicated by the presence of reticulum and transferrin receptors (TfR) (4).…”

mentioning

confidence: 99%

KCl cotransport activity in light versus dense transferrin receptor-positive sickle reticulocytes.

Franco¹,

Palascak²,

Thompson³

et al. 1995

J. Clin. Invest.

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“…It has been proposed [28] that clinical benefits would be gained from therapies which : (a) decreased cellular haemo-…”

Section: Discussionmentioning

confidence: 99%

A potent new dipeptide inhibitor of cell sickling and haemoglobin S gelation

Franklin¹,

Cotter²,

Cheetham³

et al. 1983

European Journal of Biochemistry

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A dipeptide L-lysine-L-phenylalanine is shown to inhibit both cell sickling and the gelation of solutions of sicklecell haemoglobin. The effect on deoxyhaemoglobin solutions and gels was followed by centrifugation ; a progressive inhibition of gelation was observed up to 30 mM Lys-Phe. The haemoglobin concentration at the plateau (26 g/dl) suggests that an effect might be seen in vivo if suitable concentrations of Lys-Phe (about 20 mM) can be maintained in the blood stream. Additional studies of lag time before onset of gelation support this. Oxygen dissociation curves of sickle cells showed an effect of Lys-Phe only after incubation for 3 h before measurement, the P,, decreasing from 51 mmHg (6.8 MPa) to 41 mmHg (5.5 MPa) for cells depleted of 2,3-bisphosphoglycerate.The effect of Lys-Phe on intact sickle cells was more rapid. A marked increase in the number of unsickled cells in the presence of Lys-Phe was observed after only 15 min incubation. This result, together with measurements of uptake both into the cell and onto the cell membrane shows that the compound produces a membrane-mediated antisickling effect in addition to the effect on haemoglobin in solution within the cell. The membrane effect is not due to a change in cell volume.The properties of this dipeptide may be of value in the treatment of impending and early sickle crisis.The changes in shape and flexibility of the sickle erythrocyte on deoxygenation are due to the aggregation of sickle cell haemoglobin to form extended fibrillar structures [l, 21. X-ray crystallographic studies of deoxygenated HbS [3] and X-ray diffraction of fibres [4] have revealed the sites of interaction with HbS molecules within the fibrils. These include the abnormal region of the P-chain containing valine A3(6), in one subunit, which interacts with the region 8-Phe(85)-P-Leu(SS), in a neighbouring subunit, and is the molecular basis of the hydrophobic deoxy-HbS polymerisation. Attempts to design a non-covalent and non-toxic anti-sickling agent have included examination of oligopeptides which mimic the primary sequence around these sites [S] and which might be expected to inhibit competitively the specific contacts involved in HbS polymerisation. The results obtained with these peptides were disappointing, and probably reflected an inefficient binding of competitor weakened by increased conformational entropy arising from its small size. Amino acids have also been tested for inhibitory activity [6,7] ; phenylalanine being the most effective. Amphipathic derivatives of phenylalanine [8] were more effective inhibitors of the polymerisation of deoxy-HbS, and this inhibition has been correlated with the effects of varying charge and hydrophobicity in phenylalaninerelated compounds [9 -11 1. A series of small molecules were designed to maximise hydrophobicity and red cell membrane permeabilility and these included the benzyl esters of aromatic amino acids 112). These were found to be potent inhibitors of whole cell sickling. No major effects on the properties of deoxy-HbS s...

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Requirements for therapeutic inhibition of sickle haemoglobin gelation

Cited by 134 publications

References 23 publications

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

The LSD1 inhibitor RN-1 recapitulates the fetal pattern of hemoglobin synthesis in baboons (P. anubis)

KCl cotransport activity in light versus dense transferrin receptor-positive sickle reticulocytes.

A potent new dipeptide inhibitor of cell sickling and haemoglobin S gelation

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