MUC-1 cytoplasmic domain peptides as inhibitors of cancer
View Patent ↗Peptides from the MUC1 cytoplasmic domain and methods of use therefor are described. These peptides can inhibit MUC1 oligomerization, thereby preventing tumor cell growth, inducing tumor cell apoptosis and necrosis of tumor tissue in vivo.
1. A pharmaceutical composition comprising (a) a mucin-1 (MUC1) peptide of at least 6 consecutive human MUC1 residues and no more than 20 consecutive human MUC1 residues and comprising the sequence CQC, wherein the amino-terminal cysteine of CQC is covered on its NH 2 -terminus by at least one amino acid residue that need not correspond to the native human MUC1 transmembrane sequence, and said MUC1 peptide being terminally fused to a cell delivery domain or a cell transduction domain; and (b) a pharmaceutically acceptable carrier, buffer or diluent.
2. The composition of claim 1 , wherein said MUC1 peptide contains 7 or 8 consecutive human MUC1 residues.
3. The composition of claim 1 , wherein no more than 10 consecutive residues, 11 consecutive residues, 12 consecutive residues, 13 consecutive residues, 14 consecutive residues, 15 consecutive residues, 16 consecutive residues, 17 consecutive residues, 18 consecutive residues or 19 consecutive residues of the human MUC1 sequence.
4. The composition of claim 1 , wherein said cell delivery domain or cell transduction domain is fused to the NH 2 -terminus of said MUC1 peptide.
5. The composition of claim 4 , wherein the cell transduction domain is an HIV tat cell transduction domain.
6. The composition of claim 4 , wherein said cell delivery domain is poly-D-R, poly-D-P or poly-D-K.
7. The composition of claim 1 , wherein said MUC1 peptide is at least 8 residues in length, and at least two non-adjacent residues form a bridge through their side chains.
8. The composition of claim 7 , wherein the bridge comprises a linker, chemically modified side chains, or hydrocarbon stapling.
9. The composition of claim 8 , wherein the linkers comprises modifications that stabilize an alpha-helical structure of said MUC1 peptide.
10. The composition of claim 1 , wherein said buffer comprises β-mercaptoethanol, glutathione or ascorbic acid.
11. The composition of claim 1 , wherein all the amino acid residues of said MUC1 peptide are D-amino acids.
12. The composition of claim 1 , wherein said cell delivery domain or cell transduction domain is fused to the COOH-terminus of said MUC1 peptide.
13. The composition of claim 1 , wherein all of the amino acid residues of said MUC1 peptide or L-amino acids.
14. The composition of claim 1 , wherein of the amino acid residues of said MUC1 peptide are a mix of D- and L-amino acids.
15. The composition of claim 1 , where the MUC1 peptide is NH 2 -d-RRRRRRRRR-CQCRRKNYGQLDIFP-COOH.