Small Cyclic Agonists of Iron Regulatory Hormone Hepcidin

Overview

Journal Bioorg Med Chem Lett

Specialty Biochemistry

Date 2015 Mar 28

PMID 25813158

Citations 17

Authors

Kristine Chua

Eileen Fung

Ewa D Micewicz

Tomas Ganz

Elizabeta Nemeth

Piotr Ruchala

Affiliations

Soon will be listed here.

Abstract

Minihepcidins are in vitro and in vivo active mimetics of iron-regulatory hormone hepcidin. They contain various unusual amino acids including: N-substituted, β-homo-, and d-amino acids with their combination depending on particular minihepcidin. In the current study, we sought to limit the use of unusual/more expensive amino acids derivatives by peptide cyclization. Novel cyclic mimetics of hepcidin were synthesized and tested in vitro and showed activity at low nanomolar concentration. Nonetheless, the most active cyclic compound (mHS17) is approximately ten times less active than the parental minihepcidin PR73. Collectively, our findings suggest that cyclization is viable approach in the synthesis of hepcidin mimetics.

Citing Articles

A randomized placebo-controlled clinical trial of oral green tea epigallocatechin 3-gallate on erythropoiesis and oxidative stress in transfusion-dependent β-thalassemia patients.

Settakorn K, Hantrakool S, Petiwathayakorn T, Hutachok N, Tantiworawit A, Charoenkwan P Front Mol Biosci. 2024; 10:1248742.

PMID: 38328786 PMC: 10848917. DOI: 10.3389/fmolb.2023.1248742.

The macrocycle inhibitor landscape of SLC-transporter.

Granulo N, Sosnin S, Digles D, Ecker G Mol Inform. 2024; 43(5):e202300287.

PMID: 38288682 PMC: 11475418. DOI: 10.1002/minf.202300287.

Structural basis of ferroportin inhibition by minihepcidin PR73.

Wilbon A, Shen J, Ruchala P, Zhou M, Pan Y PLoS Biol. 2023; 21(1):e3001936.

PMID: 36649314 PMC: 9882908. DOI: 10.1371/journal.pbio.3001936.

Iron Therapeutics in Women's Health: Past, Present, and Future.

Mintz J, Mirza J, Young E, Bauckman K Pharmaceuticals (Basel). 2020; 13(12).

PMID: 33302392 PMC: 7762600. DOI: 10.3390/ph13120449.

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis.

Hawula Z, Wallace D, Subramaniam V, Rishi G Pharmaceuticals (Basel). 2019; 12(4).

PMID: 31775259 PMC: 6958404. DOI: 10.3390/ph12040170.

References

Jordan J, Poppe L, Haniu M, Arvedson T, Syed R, Li V . Hepcidin revisited, disulfide connectivity, dynamics, and structure. J Biol Chem. 2009; 284(36):24155-67. PMC: 2782009. DOI: 10.1074/jbc.M109.017764. View

Nemeth E, Preza G, Jung C, Kaplan J, Waring A, Ganz T . The N-terminus of hepcidin is essential for its interaction with ferroportin: structure-function study. Blood. 2005; 107(1):328-33. PMC: 1895343. DOI: 10.1182/blood-2005-05-2049. View

Virta P, Leppanen M, Lonnberg H . Pentaerythrityltetramine scaffolds for solid-phase combinatorial chemistry. J Org Chem. 2004; 69(6):2008-16. DOI: 10.1021/jo035801+. View

Zhang L, Bulaj G . Converting peptides into drug leads by lipidation. Curr Med Chem. 2012; 19(11):1602-18. DOI: 10.2174/092986712799945003. View

Chen S, Bertoldo D, Angelini A, Pojer F, Heinis C . Peptide ligands stabilized by small molecules. Angew Chem Int Ed Engl. 2014; 53(6):1602-6. DOI: 10.1002/anie.201309459. View

Timmerman P, Beld J, Puijk W, Meloen R . Rapid and quantitative cyclization of multiple peptide loops onto synthetic scaffolds for structural mimicry of protein surfaces. Chembiochem. 2005; 6(5):821-4. DOI: 10.1002/cbic.200400374. View

Clark R, Tan C, Preza G, Nemeth E, Ganz T, Craik D . Understanding the structure/activity relationships of the iron regulatory peptide hepcidin. Chem Biol. 2011; 18(3):336-43. PMC: 3073735. DOI: 10.1016/j.chembiol.2010.12.009. View

Nemeth E, Tuttle M, Powelson J, Vaughn M, Donovan A, Ward D . Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science. 2004; 306(5704):2090-3. DOI: 10.1126/science.1104742. View

Fazio M, Oliveira Jr V, Bulet P, Miranda M, Daffre S, Miranda A . Structure-activity relationship studies of gomesin: importance of the disulfide bridges for conformation, bioactivities, and serum stability. Biopolymers. 2005; 84(2):205-18. DOI: 10.1002/bip.20396. View

10.

Baeriswyl V, Rapley H, Pollaro L, Stace C, Teufel D, Walker E . Bicyclic peptides with optimized ring size inhibit human plasma kallikrein and its orthologues while sparing paralogous proteases. ChemMedChem. 2012; 7(7):1173-6. DOI: 10.1002/cmdc.201200071. View

11.

Ganz T, Nemeth E . Hepcidin and iron homeostasis. Biochim Biophys Acta. 2012; 1823(9):1434-43. PMC: 4048856. DOI: 10.1016/j.bbamcr.2012.01.014. View

12.

Pollaro L, Raghunathan S, Morales-Sanfrutos J, Angelini A, Kontos S, Heinis C . Bicyclic peptides conjugated to an albumin-binding tag diffuse efficiently into solid tumors. Mol Cancer Ther. 2014; 14(1):151-61. DOI: 10.1158/1535-7163.MCT-14-0534. View

13.

Heinis C, Rutherford T, Freund S, Winter G . Phage-encoded combinatorial chemical libraries based on bicyclic peptides. Nat Chem Biol. 2009; 5(7):502-7. DOI: 10.1038/nchembio.184. View

14.

Tsarevsky N, Matyjaszewski K . "Green" atom transfer radical polymerization: from process design to preparation of well-defined environmentally friendly polymeric materials. Chem Rev. 2007; 107(6):2270-99. DOI: 10.1021/cr050947p. View

15.

Doyle J, Harwood B, Krishnaji S, Krishnamurthy V, Lin W, Fortin J . A two-step strategy to enhance activity of low potency peptides. PLoS One. 2014; 9(11):e110502. PMC: 4229100. DOI: 10.1371/journal.pone.0110502. View

16.

Rosi F, Triola G . Synthesis of lipidated peptides. Methods Mol Biol. 2013; 1047:161-89. DOI: 10.1007/978-1-62703-544-6_12. View

17.

Preza G, Ruchala P, Pinon R, Ramos E, Qiao B, Peralta M . Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest. 2011; 121(12):4880-8. PMC: 3225996. DOI: 10.1172/JCI57693. View

18.

Yoshida M, Akaji K, Tatsumi T, Iinuma S, Fujiwara Y, Kimura T . Synthesis of porcine brain natriuretic peptide-32 using silver tetrafluoroborate as a new deprotecting reagent of the S-trimethylacetamidomethyl group. Chem Pharm Bull (Tokyo). 1990; 38(1):273-5. DOI: 10.1248/cpb.38.273. View

19.

Biron E, Chatterjee J, Ovadia O, Langenegger D, Brueggen J, Hoyer D . Improving oral bioavailability of peptides by multiple N-methylation: somatostatin analogues. Angew Chem Int Ed Engl. 2008; 47(14):2595-9. DOI: 10.1002/anie.200705797. View

20.

White T, Renzelman C, Rand A, Rezai T, McEwen C, Gelev V . On-resin N-methylation of cyclic peptides for discovery of orally bioavailable scaffolds. Nat Chem Biol. 2011; 7(11):810-7. PMC: 3210067. DOI: 10.1038/nchembio.664. View