Peptide inhibitors of sodium channels
View Patent ↗The present invention relates to the ability of specialized non-naturally occurring peptides to bind to sodium channels and inhibit activation of the sodium channels. The invention further relates to methods for regulating of sodium absorption and fluid volume and treating disorders responsive to modulating sodium absorption by modulating the binding of specialized non-naturally occurring peptides to sodium channels.
1. A method of treating a lung disorder comprising administering to a subject in need thereof an effective amount of a fusion polypeptide and saline, wherein the fusion polypeptide comprises an epithelial sodium channel (ENaC) internalization-inducing peptide and a heterologous peptide, wherein the ENaC internalization-inducing peptide is SEQ ID NO:127, wherein the lung disorder is selected from the group consisting of cystic fibrosis, non-cystic fibrosis bronchiectasis, chronic obstructive pulmonary disease, acute bronchitis, chronic bronchitis and asthma.
2. The method of claim 1 , wherein a heterologous peptide is fused to the amino terminus of the ENaC internalization-inducing peptide or to the carboxy terminus of the ENaC internalization-inducing peptide.
3. The method of claim 1 , wherein a first heterologous peptide is fused to the amino terminus of the ENaC internalization-inducing peptide and a second heterologous peptide is fused to the carboxy terminus of the ENaC internalization-inducing peptide.
4. The method of claim 3 , wherein the first heterologous peptide and the second heterologous peptide are the same.
5. The method of claim 1 , wherein the heterologous peptide comprises one or more non-naturally occurring amino acids.
6. The method of claim 1 , wherein the heterologous peptide consists of one or more non-naturally occurring amino acids.
7. The method of claim 1 , wherein the heterologous peptide consists of two non-naturally occurring amino acids.
8. The method of claim 1 , wherein the heterologous peptide consists of D-Ala-D-Ala.
9. The method of claim 1 , wherein the fusion polypeptide consists of SEQ ID NO:128.
10. The method of claim 1 , wherein the fusion polypeptide induces cellular internalization of ENaC.
11. The method of claim 1 , wherein the fusion polypeptide induces cellular internalization of ENaC by HEK293T cells that express human alpha-, beta-, and gamma-ENaC.
12. The method of claim 1 , wherein the fusion polypeptide and the saline are administered to the lung of the subject in need thereof.
13. The method of claim 1 , wherein the saline comprises normal saline.
14. The method of claim 1 , wherein the saline comprises hypertonic saline.
15. The method of claim 9 , wherein the lung disorder is cystic fibrosis.
16. The method of claim 9 , wherein the saline comprises normal saline.
17. The method of claim 9 , wherein the saline comprises hypertonic saline.
18. The method of claim 9 , wherein the lung disorder is cystic fibrosis.