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Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload

Preza, Gloria C. and Ruchala, Piotr and Pinon, Rogelio and Ramos, Emilio and Qiao, Bo and Peralta, Michael A. and Sharma, Shantanu and Waring, Alan and Ganz, Tomas and Nemeth, Elizabeta (2011) Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. Journal of Clinical Investigation, 121 (12). pp. 4880-4888. ISSN 0021-9738. PMCID PMC3225996. https://resolver.caltech.edu/CaltechAUTHORS:20120106-071721879

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Abstract

Iron overload is the hallmark of hereditary hemochromatosis and a complication of iron-loading anemias such as β-thalassemia. Treatment can be burdensome and have significant side effects, and new therapeutic options are needed. Iron overload in hereditary hemochromatosis and β-thalassemia intermedia is caused by hepcidin deficiency. Although transgenic hepcidin replacement in mouse models of these diseases prevents iron overload or decreases its potential toxicity, natural hepcidin is prohibitively expensive for human application and has unfavorable pharmacologic properties. Here, we report the rational design of hepcidin agonists based on the mutagenesis of hepcidin and the hepcidin-binding region of ferroportin and computer modeling of their docking. We identified specific hydrophobic/aromatic residues required for hepcidin-ferroportin binding and obtained evidence in vitro that a thiol-disulfide interaction between ferroportin C326 and the hepcidin disulfide cage may stabilize binding. Guided by this model, we showed that 7–9 N-terminal amino acids of hepcidin, including a single thiol cysteine, comprised the minimal structure that retained hepcidin activity, as shown by the induction of ferroportin degradation in reporter cells. Further modifications to increase resistance to proteolysis and oral bioavailability yielded minihepcidins that, after parenteral or oral administration to mice, lowered serum iron levels comparably to those after parenteral native hepcidin. Moreover, liver iron concentrations were lower in mice chronically treated with minihepcidins than those in mice treated with solvent alone. Minihepcidins may be useful for the treatment of iron overload disorders.


Item Type:Article
Related URLs:
URLURL TypeDescription
http://dx.doi.org/10.1172/JCI57693DOIArticle
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3225996/PubMed CentralArticle
Additional Information:© 2011 American Society for Clinical Investigation. Received for publication February 21, 2011, and accepted in revised form September 21, 2011. First published November 1, 2011. We would like to acknowledge the Office of information Technology at the University of California, Irvine, and Broadcom Corp. for providing the Broadcom Distributed/Unified Cluster used for the molecular dynamics simulation and docking of the protein complex. The UCLA Jonsson Comprehensive Cancer Center and Center for AIDS Research Flow Cytometry Core Facility was instrumental for flow cytometry measurements. Matthew Schibler at the UCLA CNSI Advanced Light Microscopy Facility provided help with confocal microscopy. We thank Grace Jung for assistance with Biacore analysis and Nathan Subramaniam for providing the PDB file of his ferroportin model. The work was funded by NIH grants R01DK 082717 (to E. Nemeth) and R01 DK 065029 (to T. Ganz).
Funders:
Funding AgencyGrant Number
NIHR01 DK 082717
NIHR01 DK 065029
Issue or Number:12
PubMed Central ID:PMC3225996
Record Number:CaltechAUTHORS:20120106-071721879
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20120106-071721879
Official Citation:Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload Gloria C. Preza, Piotr Ruchala, Rogelio Pinon, Emilio Ramos, Bo Qiao, Michael A. Peralta, Shantanu Sharma, Alan Waring, Tomas Ganz, Elizabeta Nemeth
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:28684
Collection:CaltechAUTHORS
Deposited By: Ruth Sustaita
Deposited On:06 Jan 2012 15:54
Last Modified:04 Dec 2019 18:16

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