amino acid sequence including PHEX zinc binding domain and two ASARM binding domains; biodrug for bone disorders, osteoporosis
Inventors
Assignees
University of Kansas Medical Center
Publication Number
US-7825217-B2
Publication Date
2010-11-02
Expiration Date
2026-09-15
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Abstract
Polypeptides for improving bone mineralization and/or phosphate update are provided. The peptides include a PHEX zinc binding domain and two ASARM binding domains.
Core Innovation
The invention provides novel polypeptides that improve bone mineralization and phosphate uptake. These polypeptides specifically include a PHEX zinc binding domain and two ASARM binding domains, designed to bind to the ASARM motif found in MEPE or to the free ASARM peptide. By binding to ASARM, the polypeptides can reduce the concentration of biologically active ASARM peptides in vivo and in vitro, or protect MEPE from proteolysis that would otherwise release the inhibitory ASARM peptide.
The described polypeptides, such as the preferred SPR4 sequence, are concatemers of a NH-ASARM binding domain, a PHEX zinc binding domain, and a COOH-ASARM binding domain. These functional domains are derived from specific regions of the PHEX protein but are non-contiguous in native PHEX. The targeted design allows the peptides to bind both phosphorylated and non-phosphorylated ASARM motifs, and to function with the ASARM motif either within the full-length MEPE or in its cleaved, free form.
The problem addressed by the invention stems from hypomineralization defects of bone and teeth, notably as seen in conditions such as X-linked hypophosphatemic rickets, osteomalacia, and osteoporosis. In these disorders, defective PHEX leads to increased levels of inhibitory ASARM peptides, which bind phosphate and impede mineralization. Prior to this invention, there were no compositions specifically able to modulate the PHEX-MEPE-ASARM pathway by directly sequestering ASARM or mimicking PHEX binding.
Claims Coverage
There is one independent claim describing the main inventive feature covered by the patent.
Isolated polypeptide at least 80% identical to SPR4 sequence
An isolated polypeptide comprising a sequence that is at least 80% identical to TVNAFYSASTNYPRSLSYGAIGVIVGHEFTHGFDNNGRGENIADNG (SEQ. ID NO. 21), known as SPR4. - This feature covers polypeptides that have high sequence identity (80% or higher) to the stated SPR4 sequence. - The polypeptide includes essential features: two ASARM binding domains (NH- and COOH-ASARM binding domains) and a PHEX zinc binding domain within a single sequence. - The inventive feature is not limited to the exact SPR4 sequence, as identity thresholds (90%, 95%, 98%, and 100%) are recognized in dependent claims.
The claims are focused on isolated polypeptides highly similar to the SPR4 sequence, defined by the presence and sequence identity of ASARM binding and PHEX zinc binding functional domains within one contiguous sequence.
Stated Advantages
The polypeptides improve bone mineralization and renal phosphate uptake by binding and inhibiting ASARM peptides.
Administration of these polypeptides targets the PHEX-MEPE-ASARM-protease pathway in vivo and in vitro to promote mineralization and phosphate handling.
Documented Applications
Treatment of hypomineralization defects of bone and teeth, including rickets, osteomalacia, age-related bone-mineral loss disorders, and osteoporosis.
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