Hepcidin analogues and uses thereof
Inventors
Smythe, Mark Leslie • Bourne, Gregory Thomas • Vink, Simone • Frederick, Brian Troy • Madala, Praveen • Tofteng Shelton, Anne Pernille • Fog, Jacob Ulrik
Assignees
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Publication Number
US-11807674-B2
Publication Date
2023-11-07
Expiration Date
Abstract
The present invention relates, inter alia, to certain hepcidin peptide analogues, including peptides and dimers thereof, and to the use of the peptides and peptide dimers in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein.
Core Innovation
The invention relates to peptides according to formula I′ (SEQ ID NO:21), including peptides and peptide dimers, that contain two cysteine residues linked via a disulfide bond. The peptides are defined by constrained peptide sequences X′ (SEQ ID NO:13) and Y′ (SEQ ID NO:16) with enumerated allowable amino acids and optional absent positions, and the peptides may be optionally PEGylated on R1′, X′, or Y′.
A side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or a polymeric moiety. The disclosed peptides include specific sequences according to SEQ ID NO:13 and SEQ ID NO:16, and the structural definitions allow certain positions to be absent as part of the defined sequence options.
The peptides are described as ferroportin binding agents that induce ferroportin internalization and degradation, thereby lowering plasma iron. The invention relates to mini-hepcidins and hepcidin activity for treating a disease of iron metabolism, including hepcidin analogs that are Hep25-mimicking peptides.
Claims Coverage
The independent claims cover three areas: a treatment method, a pharmaceutical composition, and a manufacturing method. Across the independent claims, the core structure is a formula I′ (SEQ ID NO:21) peptide with constrained X′ (SEQ ID NO:13) and Y′ (SEQ ID NO:16) segments, two cysteine residues linked by a disulfide bond, and optional PEGylation and optional lipophilic or polymeric conjugation.
Treating a disease of iron metabolism with a formula I′ peptide
Administering an effective amount of at least one peptide according to formula I′ (SEQ ID NO:21) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises two cysteine residues linked via a disulfide bond and is optionally PEGylated on R1′, X′, or Y′, with optional conjugation of a side chain to a lipophilic substituent or a polymeric moiety; the disease of iron metabolism is selected from specified disorders.
Pharmaceutical composition comprising a formula I′ peptide
A composition comprising a peptide according to formula I′ (SEQ ID NO:21) or a pharmaceutically acceptable salt thereof, wherein the peptide comprises two cysteine residues linked via a disulfide bond and is optionally PEGylated on R1′, X′, or Y′, with optional conjugation of a side chain to a lipophilic substituent or a polymeric moiety; the peptide sequences are constrained as X′ (SEQ ID NO:13) and Y′ (SEQ ID NO:16) with enumerated allowable residues and optional absent positions.
Solid phase peptide synthesis method for a formula I′ peptide
Manufacturing a peptide according to formula I′ (SEQ ID NO:21) or a pharmaceutically acceptable salt thereof using solid phase peptide synthesis protocols, wherein the peptide comprises two cysteine residues linked via a disulfide bond and is optionally PEGylated on R1′, X′, or Y′, and wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or a polymeric moiety.
Across the independent claims, the core inventive coverage is the formula I′ (SEQ ID NO:21) peptide structure with two cysteine residues linked via a disulfide bond, together with optional PEGylation and optional lipophilic or polymeric conjugation, and defined sequence constraints on X′ and Y′; the claims further cover treatment of specified iron-metabolism diseases, composition formulations, and manufacturing via solid phase peptide synthesis protocols.
Stated Advantages
Achieves hepcidin activity defined as a dose- and time-dependent reduction of plasma iron.
Provides ferroportin internalization/degradation potency, reflected by ferroportin internalization/degradation assays in the document.
Lowering plasma iron by ferroportin binding and inducing ferroportin internalization and degradation.
Documented Applications
Treatment of diseases of iron metabolism in a subject, including hereditary hemochromatosis, hepcidin deficiency, transfusional iron overload, and thalassemia.
Formulating pharmaceutical compositions comprising the peptide of formula I′ (SEQ ID NO:21) or a pharmaceutically acceptable salt.
Manufacturing peptides of formula I′ (SEQ ID NO:21) using solid phase peptide synthesis protocols.
Pharmaceutical composition/medicament use for the treatment of iron overload diseases and related iron metabolism disorders as selected in the claims.
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