Although the root cause of sickle cell disease is the polymerization of hemoglobin S (HbS) to form fibers that make red cells less flexible, most drugs currently being assessed in clinical trials are ...targeting the downstream sequelae of this primary event. Less attention has been devoted to investigation of the multiple ways in which fiber formation can be inhibited. In this article, we describe the molecular rationale for 5 distinct approaches to inhibiting polymerization and also discuss progress with the few antipolymerization drugs currently in clinical trials.
Erythropoietin Bunn, H Franklin
Cold Spring Harbor perspectives in medicine,
2013-Mar-01, 2013-03-01, 20130301, Letnik:
3, Številka:
3
Journal Article
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Odprti dostop
During the past century, few proteins have matched erythropoietin (Epo) in capturing the imagination of physiologists, molecular biologists, and, more recently, physicians and patients. Its appeal ...rests on its commanding role as the premier erythroid cytokine, the elegant mechanism underlying the regulation of its gene, and its remarkable impact as a therapeutic agent, arguably the most successful drug spawned by the revolution in recombinant DNA technology. This concise review will begin with a synopsis of the colorful history of this protein, culminating in its purification and molecular cloning. It then covers in more detail the contemporary understanding of Epo's physiology as well as its structure and interaction with its receptor. A major part of this article focuses on the regulation of the Epo gene and the discovery of HIF, a transcription factor that plays a cardinal role in molecular adaptation to hypoxia. In the concluding section, a synopsis of Epo's role in disorders of red blood cell production will be followed by an assessment of the remarkable impact of Epo therapy in the treatment of anemias, as well as concerns that provide a strong impetus for the development of even safer and more effective treatment.
Oxygen delivery depends on hemoglobin–oxygen dissociation, which is influenced by temperature, pH, and 2,3-bisphosphoglycerate levels. Oxygen delivery must be considered in the treatment of anemia.
The mechanisms underlying Plasmodium falciparum resistance in persons with sickle trait have been under active investigation for more than a half century. This Perspective reviews progress in solving ...this challenging problem, including recent studies that have exploited the genomics and proteomics of the parasite. The formation of Hb S polymer in the parasitized AS RBC leads to impaired parasite growth and development along with enhanced clearance from the circulation and reduced deposition in deep postcapillary vascular beds. Enhanced generation of reactive oxygen species in sickled AS RBCs is a pathogenetic feature shared by parasitized thalassemic and G6PD-deficient RBCs, triggering abnormal topology of the RBC plasma membrane with decreased and disordered display of PfEMP-1, a P falciparum adhesion protein critical for endothelial adherence. A mouse model of Hb S confers host tolerance to P berghei, through inhibition of pathogenic CD8+ T cells and induction of heme oxygenase-1. An additional and apparently independent mode of protection is provided by the selective expression in AS RBCs of 2 species of microRNA that integrate into P falciparum mRNAs and inhibit translation and parasite growth.
Classification of the disorders of hemoglobin Forget, Bernard G; Bunn, H Franklin
Cold Spring Harbor perspectives in medicine,
2013-Feb-01, 2013-02-01, 20130201, Letnik:
3, Številka:
2
Journal Article
Recenzirano
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Over the years, study of the disorders of hemoglobin has served as a paradigm for gaining insights into the cellular and molecular biology, as well as the pathophysiology, of inherited genetic ...disorders. To date, more than 1000 disorders of hemoglobin synthesis and/or structure have been identified and characterized. Study of these disorders has established the principle of how a mutant genotype can alter the function of the encoded protein, which in turn can lead to a distinct clinical phenotype. Genotype/phenotype correlations have provided important understanding of pathophysiological mechanisms of disease. Before presenting a brief overview of these disorders, we provide a summary of the structure and function of hemoglobin, along with the mechanism of assembly of its subunits, as background for the rationale and basis of the different categories of disorders in the classification.
Recombinant human erythropoietin (rhEpo) has proven to be remarkably safe and effective for treatment of anemias, primarily those secondary to renal disease and malignancy. Despite the worldwide use ...of rhEpo, concerns about its cost, the need for frequent parenteral administration, and the development of anti-Epo antibodies have prompted development of improved agents to stimulate erythropoiesis. Three strategies appear to be particularly promising. The half-life of Epo in the circulation can be prolonged by the addition of N-linked carbohydrate groups, by formation of adducts with polyethylene glycol, and by preparation of Epo multimers. Second, mimetic peptides can effectively trigger signal transduction at the Epo receptor, thereby boosting red-cell production. Finally, the hypoxia inducible transcription factor (HIF) can be pharmacologically induced by oral agents, resulting in enhanced expression not only of endogenous Epo but also of other genes important in the regulation of erythropoiesis.
To the Editor:
The trials by Chertow et al. and Eckardt et al. (April 29 issue)
1,2
provide convincing evidence that vadadustat is effective in the treatment of anemia in patients with chronic kidney ...disease. This drug was compared with the commonly prescribed erythropoiesis-stimulating agent darbepoetin alfa. Darbepoetin alfa is identical in structure to recombinant human erythropoietin, except for minor amino acid substitutions that confer enhanced N-linked glycosylation and therefore a prolonged life span in the circulation. Thus, darbepoetin alfa has a high degree of specificity and, when administered at a low dose, poses a minimal risk of cardiovascular or other . . .
In 1949, the discovery that sickle hemoglobin (α
2
βS
2
) has an abnormal electrophoretic mobility prompted Linus Pauling and his colleagues to christen sickle cell anemia “a molecular disease.”
1
...The ensuing five decades have produced a wealth of information on the mechanisms by which a single base substitution in the gene encoding the human β-globin subunit, with the resulting replacement of β6 glutamic acid by valine, leads to the protean and devastating clinical manifestations of sickle cell disease. Until recently there was a disappointing lag in the application of this knowledge to the design of safe and effective . . .
The issue of treating sickle cell disease with drugs that increase hemoglobin oxygen affinity has come to the fore with the US Food and Drug Administration approval in 2019 of voxelotor, the only ...antisickling drug approved since hydroxyurea in 1998. Voxelotor reduces sickling by increasing the concentration of the nonpolymerizing, high oxygen affinity R (oxy) conformation of hemoglobin S (HbS). Treatment of sickle cell patients with voxelotor increases Hb levels and decreases indicators of hemolysis, but with no indication as yet that it reduces the frequency of pain episodes. In this study, we used the allosteric model of Monod, Wyman, and Changeux to simulate whole-blood oxygen dissociation curves and red cell sickling in the absence and presence of voxelotor under the in vivo conditions of rapid oxygen pressure decreases. Our modeling agrees with results of experiments using a new robust assay, which shows the large, expected decrease in sickling from the drug. The modeling indicates, however, that the increase in oxygen delivery from reduced sickling is largely offset by the increase in oxygen affinity. The net result is that the drug increases overall oxygen delivery only at the very lowest oxygen pressures. However, reduction of sickling mitigates red cell damage and explains the observed decrease in hemolysis. More importantly, our modeling of in vivo oxygen dissociation, sickling, and oxygen delivery suggests that drugs that increase fetal Hb or decrease mean corpuscular hemoglobin concentration (MCHC) should be more therapeutically effective than drugs that increase oxygen affinity.
•Voxelotor therapy reduces sickling and increases hemoglobin, but oxygen delivery to tissues is offset by increased hemoglobin O2 affinity.•Drugs that reduce sickling by increasing HbF or decreasing MCHC should be more effective than drugs that increase O2 affinity.
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