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Conjugated hepcidin mimetics

A technology of hepcidin and analogues, applied in the field of hepcidin peptide analogues, which can solve problems such as high product costs

Pending Publication Date: 2022-07-08
PROTAGONIST THERAPEUTICS INC
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Hepcidin has a number of limitations that limit its use as a drug, including a process that is difficult to synthesize due in part to aggregation and precipitation of the protein during folding, which in turn leads to high product costs

Method used

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  • Conjugated hepcidin mimetics
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Examples

Experimental program
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Effect test

Embodiment 1

[0560] Synthesis of Peptide Analogs

[0561] Unless otherwise indicated, the reagents and solvents used below were commercially available as standard laboratory reagents or analytical grade and used without further purification.

[0562] Solid Phase Synthesis Procedure for Peptides

[0563]Peptide analogs of the invention were chemically synthesized using an optimized 9-fluorenylmethoxycarbonyl (Fmoc) solid phase peptide synthesis protocol. For C-terminal amides, rink-amide resins were used, although wang and trityl resins were also used to generate C-terminal acids. Side chain protecting groups are as follows: Glu, Thr and Tyr: O-tert-butyl; Trp and Lys: t-Boc (tert-butoxycarbonyl); Arg: N-γ-2,2,4,6,7-penta Methyldihydrobenzofuran-5-sulfonyl; His, Gln, Asn, Cys: trityl. For selective disulfide bridge formation, Acm (acetamidomethyl) was also used as a Cys protecting group. For coupling, a 4- to 10-fold excess of a solution containing Fmoc amino acid, HBTU and DIPEA (1:1...

Embodiment 2

[0584] Peptide analog activity

[0585] Peptide analogs were tested in vitro to induce internalization of human ferroportin. After internalization, the peptide is degraded. This assay measures the decrease in acceptor fluorescence.

[0586] The cDNA encoding human ferroportin (SLC40A1) was cloned from the cDNA clone of Origene (NM_014585). The DNA encoding the ferroportin was amplified by PCR using primers that also encoded terminal restriction sites for subcloning, but without stop codons. The ferroportin receptor was subcloned into a mammalian GFP expression vector containing a neomycin (G418) resistance marker such that the reading frame of the ferroportin was fused in-frame with the GFP protein. The fidelity of the protein-encoding DNA was confirmed by DNA sequencing. HEK293 cells were used to transfect the ferroportin-GFP receptor expression plasmid. Cells were grown in growth medium according to standard protocols and transfected with plasmids using Lipofectamine (m...

Embodiment 3

[0593] Hepcidin inhibition in polycythemia vera

[0594] The hepcidin analogs of the invention were tested for activity in polycythemia vera as described in Casu et al., Blood. 2016;128(2):265-276.

[0595] Hepcidin is a 25 amino acid peptide that controls systemic iron homeostasis and is produced by the liver in response to plasma iron concentrations and iron stores. Hepcidin inhibits the cellular iron exporter ferroportin (FPN-1), which is expressed on the surface of cells involved in iron absorption, recycling and storage. In a murine model of polycythemia vera, hepcidin regulates systemic iron restriction, and exogenous administration of exogenous hepcidin mimetics reduces Hgb concentrations and splenomegaly (Casu et al., Blood. 2016; 128(2 ): 265-276).

[0596] When JAK2 is constitutively activated, erythropoietin-independent red blood cell production is triggered, resulting in polycythemia. A method to prevent the effects of mutant Jak2 is to induce iron restriction w...

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Abstract

The invention provides hepcidin analogs and related pharmaceutical compositions and uses thereof in the treatment of polycythemia vera.

Description

[0001] CROSS-REFERENCE TO RELATED APPLICATIONS [0002] This application claims US Provisional Application No. 62 / 895,201, filed September 3, 2019, US Provisional Application No. 62 / 983,515, filed February 28, 2020, US Provisional Application No. 63 / 020,945, filed May 6, 2020 and priority to US Provisional Application No. 63 / 059,747, filed July 31, 2020, all of which are incorporated herein by reference in their entirety. [0003] sequence listing [0004] This application contains a Sequence Listing submitted electronically in ASCII format, which is incorporated herein by reference in its entirety. Said ASCII copy created on September 1, 2020 is named PRTH_037_05WO_ST25.txt and is 25KB in size. technical field [0005] In particular, the present invention relates to certain hepcidin peptide analogs, including peptide monomers and peptide dimers, and conjugates and derivatives thereof, and to the use of said peptide analogs in the treatment and / or prevention of polycythemia ...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/575
CPCA61P7/00C07K14/575A61K38/22A61K2300/00A61K38/00A61K47/60C07K7/06C07K7/08
Inventor 大卫·Y·刘格雷戈里·托马斯·伯恩鲁帕·塔拉纳特苏尼尔·库马尔·古普塔尼希特·巴楚拉尔·莫迪
Owner PROTAGONIST THERAPEUTICS INC
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