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Hepcidin Therapeutics

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Hepcidin Therapeutics pharmaceuticals Review Hepcidin Therapeutics Angeliki Katsarou and Kostas Pantopoulos * Lady Davis Institute for Medical Research, Jewish General Hospital, Department of Medicine, McGill University, Montreal, QC H3T 1E2, Canada; [email protected] * Correspondence: [email protected]; Tel.: +1-(514)-340-8260 (ext. 25293) Received: 3 November 2018; Accepted: 19 November 2018; Published: 21 November 2018 Abstract: Hepcidin is a key hormonal regulator of systemic iron homeostasis and its expression is induced by iron or inflammatory stimuli. Genetic defects in iron signaling to hepcidin lead to “hepcidinopathies” ranging from hereditary hemochromatosis to iron-refractory iron deficiency anemia, which are disorders caused by hepcidin deficiency or excess, respectively. Moreover, dysregulation of hepcidin is a pathogenic cofactor in iron-loading anemias with ineffective erythropoiesis and in anemia of inflammation. Experiments with preclinical animal models provided evidence that restoration of appropriate hepcidin levels can be used for the treatment of these conditions. This fueled the rapidly growing field of hepcidin therapeutics. Several hepcidin agonists and antagonists, as well as inducers and inhibitors of hepcidin expression have been identified to date. Some of them were further developed and are currently being evaluated in clinical trials. This review summarizes the state of the art. Keywords: iron metabolism; hepcidin; ferroportin; hemochromatosis; anemia 1. Systemic Iron Homeostasis Iron is an essential constituent of cells and organisms and participates in vital biochemical activities, such as DNA synthesis, oxygen transfer, and energy metabolism. The biological functions of iron are based on its capacity to interact with proteins and on its propensity to switch between the ferrous (Fe2+) and ferric (Fe3+) oxidation states. In spite of the high abundance of iron on the earth’s crust, its bioavailability is limited by the fact that under aerobic conditions, ferrous iron is readily oxidized to insoluble ferric. Accumulation of excess iron in cells is toxic, because “free” ferrous iron catalyzes the generation of hydroxyl radicals via Fenton chemistry, which attack and inactivate cellular macromolecules [1]. The intricate chemistry of iron poses a major challenge for iron homeostasis: To satisfy metabolic needs and limit toxic side effects [2]. Mammals have developed mechanisms to efficiently acquire and retain dietary iron in the body and store, but not excrete the iron excess. Approximately 70% of body iron (~3–5 g in adult humans) is bound to heme and used in hemoglobin of red blood cells [3]. Another 2–3% is present in muscles, where it is mostly utilized in the heme moiety of myoglobin. Excess of body iron accumulates in liver hepatocytes, where it is stored within ferritin and can be mobilized for erythropoiesis under iron deficiency. On a daily basis, erythropoiesis requires up to 30 mg of iron, while non-erythroid cell requirements are ~5 mg. Bone marrow erythroblasts and non-erythroid cells in other tissues acquire iron from plasma transferrin. This protein not only serves as an iron carrier, but also keeps circulating iron in a redox-inactive state. Under physiological conditions, only ~30% of transferrin molecules are saturated with Fe3+ and the iron-free apo-transferrin offers a redox buffering capacity. The iron content of transferrin (~3 mg) represents a small, but a highly dynamic fraction of body iron, which turns over more than 10 times per day to satisfy metabolic needs. It is mainly replenished by iron recycled from effete red blood cells via tissue macrophages during erythrophagocytosis. Dietary iron absorption (1–2 mg/day) Pharmaceuticals 2018, 11, 127; doi:10.3390/ph11040127 www.mdpi.com/journal/pharmaceuticals Pharmaceuticals 2018, 11, 127 2 of 30 Pharmaceuticals 2018, 11, 2 of 33 contributescontributes toto the the buildup buildup of ironof iron stores stores during during development; development; in adults in it mainlyadults servesit mainly to compensate serves to forcompensate non-specific for ironnon-specific losses, for iron instance losses, viafor bleedinginstance orvia cell bleeding desquamation. or cell desquamation. 2.2. Hepcidin: The Key Iron Regulatory Hormone SerumSerum ironiron levels are under the control of hepcidin, a liver-derived peptide hormone and master regulatorregulator ofof iron iron metabolism metabolism [4 ].[4]. It operates It operates by binding by binding to the to iron the exporter iron exporter ferroportin ferroportin in iron-releasing in iron- targetreleasing cells, target mainly cells, tissue mainly macrophages tissue macrophages and duodenal and enterocytes,duodenal enterocytes, but also other but cellalso types other (Figurecell types1). The(Figure binding 1). The of binding hepcidin of hepcidin occludes occludes iron efflux iron [5 efflux] and [5] triggers and triggers ubiquitination, ubiquitination, internalization internalization and lysosomaland lysosomal degradation degradation of ferroportin of ferroportin [6]. [6]. This This leads leads to to intracellular intracellular iron iron retention retention andand eventuallyeventually toto hypoferremia.hypoferremia. FigureFigure 1.1. Physiological and pharmacological regulation of hepcidin activity. HepcidinHepcidin isis synthesizedsynthesized inin hepatocyteshepatocytes inin responseresponse toto ironiron oror inflammatoryinflammatory stimuli.stimuli. It operatesoperates byby targetingtargeting thethe ironiron exporterexporter ferroportinferroportin inin tissuetissue macrophagesmacrophages andand duodenalduodenal enterocytes.enterocytes. The bindingbinding ofof hepcidinhepcidin promotespromotes ferroportinferroportin degradation,degradation, ironiron retentionretention inin targettarget cellscells andand hypoferremia.hypoferremia. SuppressionSuppression of hepcidinhepcidin byby erythropoieticerythropoietic stimuli allowsallows ironiron effluxefflux fromfrom cellscells intointo plasmaplasma viavia ferroportin.ferroportin. TheThe expressionexpression ofof hepcidinhepcidin can bebe manipulatedmanipulated pharmacologically with drugs that target hepatocytes (blue arrows). HepcidinHepcidin responses can bebe mimickedmimicked byby hepcidinhepcidin agonistsagonists (orange(orange circles)circles) oror ferroportinferroportin inhibitorsinhibitors (light(light blueblue squares).squares). Conversely,Conversely, hepcidinhepcidin responsesresponses cancan bebe antagonizedantagonized byby directdirect hepcidinhepcidin inhibitorsinhibitors (red(red squares)squares) oror ferroportin-bindingferroportin-binding hepcidinhepcidin inhibitorsinhibitors (green(green squares).squares). The insetsinsets highlighthighlight majormajor physiologicalphysiological hepcidinhepcidin inducersinducers oror suppressors,suppressors, asas wellwell asas clinically relevant drugsdrugs thatthat modulatemodulate the hepcidin-ferroportinhepcidin-ferroportin axis and are currentlycurrently beingbeing evaluatedevaluated inin randomizedrandomized controlled trials for thethe treatmenttreatment ofof hepcidin-relatedhepcidin-related disordersdisorders (“hepcidinopathies”).(“hepcidinopathies”). Tf,Tf, transferrin.transferrin. TheThe HAMP gene encodes pre-pro-hepcidin, anan 84 amino acids long precursor, which is primarily expressedexpressed byby hepatocytes in the liver, andand at much lower levels by other cells in extrahepatic tissues. Pre-pro-hepcidinPre-pro-hepcidin is processedprocessed toto pro-hepcidinpro-hepcidin uponupon removalremoval ofof itsits endoplasmicendoplasmic reticulumreticulum targetingtargeting sequence,sequence, consisting consisting of of 24 24 N-terminal N-terminal amino amino acids. acids. Further Further cleavage cleavage at the C-terminus at the C-terminus yields matures, yields matures,bioactive bioactivehepcidin, hepcidin, an evolutionary an evolutionary conserved, conserved, cysteine-rich cysteine-rich peptide peptide of 25-amino of 25-amino acids acidswith withantimicrobial antimicrobial properties. properties. It folds It folds to a to distorted a distorted β-sheetβ-sheet with with an an unusual unusual disulfide disulfide bridge bridge between adjacentadjacent C13-C14 at the turn of a hairpin loop; accordingaccording to this model, the structure is stabilized by furtherfurther disulfidedisulfide bondingbonding betweenbetween C7-C23,C7-C23, C10-C22C10-C22 andand C11-C19C11-C19 [[7]7] (Figure(Figure2 2,, left). left). An An alternative alternative structuralstructural model model postulates postulates disulfide disulfide bond bond connectivity connectivity between between C7-C23, C7-C23, C10-C13, C10-C13, C11-C19 C11-C19 and C14- and C14-C22C22 [8] (Figure [8] (Figure 2, right).2, right). Interestingly, Interestingly, the the structural structural organization organization of of hepcidin hepcidin based onon disulfidedisulfide bonding is not essential for iron-regulatory function, since the substitution of cysteines or the deletion of cysteine-containing segments do not impair hormonal activity [9,10]. Pharmaceuticals 2018, 11, 127 3 of 30 bonding is not essential for iron-regulatory function, since the substitution of cysteines or the deletion of cysteine-containing segments do not impair hormonal activity [9,10]. Pharmaceuticals 2018, 11, 3 of 33 Figure 2. Proposed crystal structures of hepcidin. A structure with disulfide disulfide bonds between C7-C23, C10-C22, C13-C14 and C11-C19 (PDB ID: 1M4F) is shown on the left.left. An alternative structure with disulfidedisulfide bondsbonds betweenbetween C7-C23, C7-C23,
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