Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
  • Clinical Research and Public Health
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Video Abstracts
  • Reviews
    • View all reviews ...
    • Pancreatic Cancer (Jul 2025)
    • Complement Biology and Therapeutics (May 2025)
    • Evolving insights into MASLD and MASH pathogenesis and treatment (Apr 2025)
    • Microbiome in Health and Disease (Feb 2025)
    • Substance Use Disorders (Oct 2024)
    • Clonal Hematopoiesis (Oct 2024)
    • Sex Differences in Medicine (Sep 2024)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Clinical Research and Public Health
    • Research Letters
    • Letters to the Editor
    • Editorials
    • Commentaries
    • Editor's notes
    • Reviews
    • Viewpoints
    • 100th anniversary
    • Top read articles

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Video Abstracts
  • In-Press Preview
  • Clinical Research and Public Health
  • Research Letters
  • Letters to the Editor
  • Editorials
  • Commentaries
  • Editor's notes
  • Reviews
  • Viewpoints
  • 100th anniversary
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Publication alerts by email
  • Advertising
  • Job board
  • Contact
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, … , Tomas Ganz, Elizabeta Nemeth
Gloria C. Preza, … , Tomas Ganz, Elizabeta Nemeth
Published November 1, 2011
Citation Information: J Clin Invest. 2011;121(12):4880-4888. https://doi.org/10.1172/JCI57693.
View: Text | PDF
Research Article Hematology Article has an altmetric score of 12

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

  • Text
  • PDF
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.

Authors

Gloria C. Preza, Piotr Ruchala, Rogelio Pinon, Emilio Ramos, Bo Qiao, Michael A. Peralta, Shantanu Sharma, Alan Waring, Tomas Ganz, Elizabeta Nemeth

×

Figure 3

A RosettaDock model of the interaction between hepcidin and the ferroportin loop surrounding C326.

Options: View larger image (or click on image) Download as PowerPoint
A RosettaDock model of the interaction between hepcidin and the ferropor...
(A) Plot of the full set of 1,000 structures generated in the RosettaDock refinement run. The energy score versus the root mean square (rms) distance from the starting structure shows the optimal energetic funnel of low-energy structures clustered around a single position. The plot indicates that the docking algorithm has reached a good local minimum and that the lowest scoring (lowest free energy) structures are the most stable. The second-lowest energy structure was most compatible with our mutagenesis data and is presented in B. (B) Hepcidin sequence is shown in pink, with yellow disulfide connectivities. Ferroportin extracellular loop is shown in cyan, transmembrane helices are shown in gray, and the sulfur of C326 is shown in yellow. The strongly interacting side chain pairs are displayed in thicker lines. Hydrogens are not shown. The model identified hydrophobic interactions between H3, F4, and I6 on hepcidin and Y333 on ferroportin and pi-stacking interaction between F9 and F324. The interaction of aromatic residues on the hepcidin and ferroportin surfaces brings C326 close to the disulfide network of hepcidin (disulfide cage), raising the possibility of transient disulfide exchange.

Copyright © 2025 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts

Referenced in 50 patents
146 readers on Mendeley
See more details