Compounds modulators of VEGF activity and uses thereof
Inventors
D'Andrea, Luca Domenico • Pedone, Carlo • Turco, Maria Caterina
Assignees
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Publication Number
US-9737622-B2
Publication Date
2017-08-22
Expiration Date
Abstract
Compounds of general formula (1): X1Y1X2Y2X3Y3X4Y4Y5X5X6Y6X7Y7X8X9X10 wherein X1-X10 are any natural or unnatural amino acids and Y1 is Gln; Y2 is Met or Leu; Y3 is He; Y4 is Pro or Ser; Y5 is His or Gly; Y6 is Gln or Pro; Y7 is He or Tyr or their homolog or ortolog are described; these compounds are able to bind to the VEGF receptors and to modulate the angiogenesis mediated by the VEG.
Core Innovation
The invention relates to VEGF-receptor binding synthetic peptides derived from the VEGF β-hairpin region (79-92), and a PlGF fragment. The peptides are provided according to a general formula (1) and include preferred cyclic and linear sequences, including sequences identified as SEQ ID Nos 1-24. The peptide sequences are designed to include a hydrophobic cluster and a disulfide bond for structural stabilization and receptor binding.
The disclosed peptides include cyclic disulfide-containing sequences selected from KQCMWIKPHQGQWTCTS [SEQ ID No 2] and KQLLWIRSGDRPWYYTS [SEQ ID No 3]. The content also describes other peptide sequences, including KQCLWIRSGDRPWYCTS [SEQ ID No 4]. The peptides are described in the context of VEGF receptors including VEGFR1, VEGFR2, VEGFR3, and neuropilins (NRP1, NRP2), and are associated with VEGF-dependent angiogenesis biology.
The document further discloses uses for the peptides including medical treatment of VEGF-dependent angiogenesis disorders and imaging of VEGF-receptor-overexpressing pathologies. Imaging is described using labeled imaging agents, including contrast agents and paramagnetic agents, to target angiogenic vasculature. Biological data are described, including that peptide #3 shows pro-angiogenic/VEGF-like agonist effects, while peptides #1/#2/#4 show anti-angiogenic/inhibitory effects and antagonize VEGF effects in described assays.
Claims Coverage
The independent claim covers imaging by administering a VEGF-receptor-binding peptide selected from two specified cyclic sequences and determining VEGF receptor expression after administration. The claim set includes three dependent refinements, including labeling of the peptide, specifying label type (contrast or paramagnetic agent), and narrowing the imaging target to angiogenic vasculature.
Imaging VEGF receptor expression with a selected VEGF-receptor-binding peptide
A method for imaging an expression level of VEGF receptors comprising administering a peptide having the sequence selected from the group consisting of KQCMWIKPHQGQWTCTS [SEQ ID No 2] (cyclic: Cys residues make a disulfide bond) and KQLLWIRSGDRPWYYTS [SEQ ID No 3] to a subject and determining the expression level of VEGF receptors following administration of the peptide.
Labeled VEGF-receptor-binding peptide for imaging
The method wherein the peptide is labeled.
Contrast or paramagnetic label for imaging
The method wherein the label is a contrast or a paramagnetic agent.
Imaging angiogenic vasculature
The method further includes imaging angiogenic vasculature.
Overall, the claims cover imaging VEGF receptor expression by administering one of two specified cyclic disulfide-forming VEGF-receptor-binding peptide sequences and determining VEGF receptor expression post-administration, with refinements requiring a labeled peptide, specifying contrast or paramagnetic label types, and optionally limiting imaging to angiogenic vasculature.
Stated Advantages
Enables imaging of an expression level of VEGF receptors after administration of a VEGF-receptor-binding peptide.
Enables imaging using a labeled peptide, including contrast or paramagnetic agents.
Enables imaging of angiogenic vasculature.
Documented Applications
Medical treatment of VEGF-dependent angiogenesis disorders.
Diagnosis and imaging of VEGF-receptor-overexpressing pathologies.
Imaging using labeled imaging agents to target angiogenic vasculature, including contrast or paramagnetic agents.
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