Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia

Manolova, Vania; Nyffenegger, Naja; Flace, Anna; Altermatt, Patrick; Varol, Ahmet; Doucerain, Cédric; Sundström, Hanna; Dürrenberger, Franz

doi:10.1172/jci129382

Cited by 68 publications

(114 citation statements)

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“…Ferroportin is the only known iron transporter in mammals and is mainly expressed in tissues of iron absorption (duodenum), recycling and storage (liver, spleen and mononuclear phagocyte system), mediating the transfer of iron into the blood . In vitro, VIT‐2763 inhibited cellular iron efflux with a potency comparable to that of hepcidin, the natural inhibitor of ferroportin, and in preclinical studies, VIT‐2763 demonstrated good oral bioavailability . In 14‐day toxicity studies in Wistar rats, the “no observed adverse effect level” was >600 mg/kg; in longer‐term studies, no dose‐limiting toxicity was observed.…”

Section: Introductionmentioning

confidence: 99%

“…In 14‐day toxicity studies in Wistar rats, the “no observed adverse effect level” was >600 mg/kg; in longer‐term studies, no dose‐limiting toxicity was observed. Dose‐limiting effects in rodents were related to the pharmacology of VIT‐2763 (restricted iron uptake) and resulting iron deficiency anemia and subsequent secondary effects thereof . In a mouse model of NTDT, VIT‐2763 decreased serum iron levels, ameliorated anemia and improved ineffective erythropoiesis .…”

Section: Introductionmentioning

confidence: 99%

“…Dose‐limiting effects in rodents were related to the pharmacology of VIT‐2763 (restricted iron uptake) and resulting iron deficiency anemia and subsequent secondary effects thereof . In a mouse model of NTDT, VIT‐2763 decreased serum iron levels, ameliorated anemia and improved ineffective erythropoiesis . Thus, limiting iron availability for erythropoiesis via ferroportin inhibition is a potential approach to treating NTDT…”

Section: Introductionmentioning

confidence: 99%

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Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Richard

Lier²,

Roubert

et al. 2019

American J Hematol

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Restriction of iron availability by ferroportin inhibition is a novel approach to treating non-transfusion-dependent thalassemia (β-thalassemia intermedia). This first-in-human, Phase I study (https://www.clinicaltrialsregister.eu; EudraCT no. 2017-003395-31) assessed the safety, tolerability, pharmacokinetics and pharmacodynamics of singleand multiple-ascending doses (SAD and MAD) of the oral ferroportin inhibitor, VIT-2763, in healthy volunteers. Participants received VIT-2763 5/15/60/120/240 mg or placebo in the SAD phase and VIT-2763 60/120 mg once daily, VIT-2763 60/120 mg twice daily, or placebo for 7 days in the MAD phase. Seventy-two participants completed treatment. VIT-2763 was well tolerated and demonstrated a similar safety profile to the placebo. There were no serious or severe adverse events, or discontinuations due to adverse events. VIT-2763 absorption was relatively fast, with detectable levels 15 to 30 minutes post-dose. Following multiple dosing there was no apparent change in absorption and accumulation was minimal. Mean elimination halflife was 1.9 to 5.3 hours following single dosing, and 2.1 to 3.8 hours on Day 1 and 2.6 to 5.3 hours on Day 7, following repeated dosing. There was a temporary decrease in mean serum iron levels with VIT-2763 single doses ≥60 mg and all multiple doses; mean calculated transferrin saturation (only assessed following multiple dosing) also temporarily decreased. A shift in mean serum hepcidin peaks followed administration of all iron-lowering doses of VIT-2763. This effect was less pronounced after 7 days of multiple dosing (aside from with 120 mg once daily). These results support the initiation of clinical studies in patients with non-transfusion-dependent thalassemia and documented iron overload due to ineffective erythropoiesis.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Richard

Lier²,

Roubert

et al. 2019

American J Hematol

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“…We determined here that hepcidin binding to FPN is greatly potentiated by iron itself, potentially due to the stabilizing effect iron has on the hepcidin-binding site of FPN. With iron, the binding affinity of hepcidin falls in a range concordant with the concentration of hepcidin observed in While the precise structural determinants underpinning hepcidin binding to FPN will require future studies capturing a high resolution hepcidin-ferroportin complex, the allosteric potentiation of hepcidin activity by iron may have immediate consequences for the development of hepcidin mimetics currently in clinical trials 16 . Furthermore, hepcidin antagonism by direct targeting of FPN may require molecules with high potency to overcome the nanomolar effect of the hormone in the presence of iron.…”

Section: Discussionmentioning

confidence: 89%

“…By contrast, inappropriate elevation of hepcidin levels yields iron-restricted anemia 14,15 . Although several approaches to restore aberrant FPN function have been evaluated in clinical trials [16][17][18] , none have thus far succeeded.…”

Section: Introductionmentioning

confidence: 99%

Structure of human ferroportin bound to hepcidin reveals mechanisms of iron homeostasis

Billesboelle

Azumaya

Kretsch

et al. 2020

Preprint

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The serum iron level in humans is tightly controlled by the action of the hormone hepcidin on the iron efflux transporter ferroportin. Hepcidin negatively regulates iron absorption and iron recycling by inducing ferroportin internalization and degradation. Aberrant ferroportin activity can lead to diseases of iron overload, like hemochromatosis, or iron limitation anemias. The molecular basis of ferroportin-mediated iron transport and regulation by hepcidin remain incompletely understood. Here, we combine cryo-electron microscopy, molecular dynamics simulations, and biochemical experiments to decipher molecular details of iron recognition and hepcidin binding to ferroportin. Iron binds to a conserved cavity in the C-domain of ferroportin, in a site unique within the broader major facilitator superfamily of transporters. We further show that hepcidin binding to ferroportin is allosterically coupled to iron binding, with an 80-fold increase in hepcidin affinity in the presence of iron. Hepcidin binds to the outward open conformation of ferroportin in a region adjacent to the iron-binding site in the C-domain. These results suggest a new model for hepcidin regulation of ferroportin, where only iron loaded ferroportin molecules are targeted for degradation. More broadly, our structural and functional insights are likely to enable more targeted manipulation of the hepcidin-ferroportin axis in disorders of iron homeostasis.Our structure reveals a monomeric FPN bound to a single Fab45D8 molecule, which recognizes a short alpha helical segment in extracellular loop 2 (ECL2) ( Fig. 1a and Supplementary Fig. 5).Similar to other MFS transporters, FPN contains twelve transmembrane (TM) helices arranged in two domains. Both the N-terminal and C-terminal domains are composed of six helices, with a large central cavity that in our structure is open to the extracellular side and closed intracellularly ( Fig. 1b). Ferroportin shares significant structural similarity with the bacterial bbFPN transporter, with an overall root mean squared deviation (RMSD) of 2.0 Å when compared to the outward-open conformation of bbFPN (Fig. 1c). The overall backbone conservation is even higher within the isolated C-terminal domain (RMSD 1.4 Å). Unlike most other MFS transporters, the alpha helix of FPN TM7 is interrupted by a short non-helical stretch of six residues. This unique feature, previously posited to be important in iron binding 24 , is shared between human FPN and bbFPN.Several interacting residues define an intracellular gate that keeps the N-and C-domains of 151 min at RT, and fluorescence polarization was recorded on a Biotek Synergy H4 (Agilent) in polarization mode using fixed bandpass filters with λ ex of 484 nm and λ em of 520 nm.Analytical fluorescence size exclusion chromatography (FSEC) was performed by mixing 25 µg of NW11-FPN with 2x fold molar excess of RhoG-Hepcidin in sample buffer comprised of 20 mM HEPES (pH 7.50), 100 mM NaCl and 10 µM CoCl 2 . Samples were incubated for 20 min on ice and 1.5 x molar excess of Fab45D8,...

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Beyond Inhibition

Kostić

Jones

2022

Protein Homeostasis in Drug Discovery

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Oral ferroportin inhibitor ameliorates ineffective erythropoiesis in a model of β-thalassemia

Cited by 68 publications

References 52 publications

Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Oral ferroportin inhibitor VIT‐2763: First‐in‐human, phase 1 study in healthy volunteers

Structure of human ferroportin bound to hepcidin reveals mechanisms of iron homeostasis

Beyond Inhibition

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