Mucin hypersecretion inhibitors and methods of use
Peptides are provided that comprise less than 24 amino acids. The peptides have an amino acid sequence selected from the group consisting of: (a) an amino acid sequence having from 4 to 6 contiguous amino acids of a reference sequence PEPTIDE 1; (b) an amino acid sequence substantially identical to the sequence defined in (a); and (c) a variant of the amino acid sequence defined in (a). Also provided is a non-myristoylated MANS peptide. Various methods of using the peptides are also provided.
1. An N-terminal- and/or C-terminal-chemically modified peptide, which peptide consists of an amino acid sequence consisting of
a contiguous 4 to 6 amino acid segment of a reference sequence, GAQFSKTAAKGEAAAERPGEAAVA (SEQ ID NO:1), wherein the amino acid segment is selected from the group consisting of SEQ ID NO: 176 to SEQ ID NO: 180, SEQ ID NO: 196 to SEQ ID NO: 199, SEQ ID NO: 217 and SEQ ID NO: 219;
wherein
(i) the C-terminal amino acid of said chemically modified peptide is chemically modified and the N-terminal amino acid of the peptide is alkylated or acylated at the N-terminal amino group;
or
(ii) the C-terminal amino acid of said chemically modified peptide is not chemically modified and the N-terminal amino acid of the peptide is alkylated or acylated at the N-terminal amino group and is not myristoylated;
with the proviso that said chemically modified peptide contains no more than 6 amino acids; and
wherein said chemically modified peptide has a mucin hypersecretion-inhibiting effect when administered to a mammal in a mucin hypersecretion-inhibiting amount.
2. The modified peptide of claim 1 , wherein the amino acid sequence of the peptide includes the contiguous residues AKGE (SEQ ID NO: 219) of the reference sequence.
3. The modified peptide of claim 1 , wherein the N-terminal amino acid of the peptide is acetylated at the N-terminal amino group.
4. The modified peptide of claim 1 , wherein said peptide is acetyl-PEPTIDE 179, acetyl-PEPTIDE 219, or acetyl-PEPTIDE 219-NH 2 .
5. The modified peptide of claim 1 , wherein the amino acid sequence is selected from the group consisting of the amino acid sequence of SEQ ID NO: 178 to SEQ ID NO: 180, SEQ ID NO: 198, SEQ ID NO: 199 and SEQ ID NO: 219.
6. The modified peptide of claim 1 , wherein the N-terminal amino acid is alkylated at the N-terminal amine with a C1 to C24 aliphatic alkyl group, a linear 2-(C1 to C24 aliphatic alkyl)oxyethyl group, or an omega-methoxy-poly(ethyleneoxy) n -ethyl group, where n is from 0 to 10.
7. The modified peptide of claim 1 , wherein the N-terminal amino acid is acylated at the N-terminal amine with a-trifluoroacetic acid, benzoic acid, or a C 1 to C 24 aliphatic carboxylic acid.
8. The modified peptide of claim 1 , wherein the C-terminal amino acid of the peptide is amidated or esterified at the C-terminal carboxyl group.
9. The modified peptide of claim 1 , wherein the C-terminal amino acid is amidated at the C-terminal carboxyl group with ammonia, a C1 to C24 aliphatic alkyl amine, a hydroxyl-substituted C2 to C24 aliphatic alkyl amine, a linear 2-(C1 to C24 aliphatic alkyl)oxyethylamine group, or an omega-methoxy-poly(ethyleneoxy) n -ethylamine group, where n is from 0 to 10.
10. The modified peptide of claim 1 , wherein the C-terminal amino acid is esterified at the C-terminal carboxyl group with a C1 to C24 aliphatic alkyl alcohol or a 2-(omega-methoxy-poly(ethyleneoxy) n )-ethanol group, where n is from of 0 to 10.
11. The modified peptide of claim 1 , wherein the modified peptide exhibits at least one of the properties of (a) greater mucin hypersecretion-inhibiting effect on a mammal than a peptide with reference sequence, GAQFSKTAAKGEAAAERPGEAAVA (SEQ ID NO:1), wherein the N-terminal amino acid of the reference sequence is myristoylated, when administered to said mammal at equal concentrations or (b) greater aqueous solubility than SEQ ID NO:1, wherein the N-terminal amino acid of the reference sequence is myristoylated, at equal concentrations in the same liquid.
12. A pharmaceutical composition comprising the peptide of claim 1 and a pharmaceutically acceptable carrier.
13. The pharmaceutical composition of claim 12 , wherein said composition is suitable for pulmonary administration.
14. An N-terminal- and/or C-terminal-chemically modified peptide, which peptide consists of an amino acid sequence selected from
a contiguous 4 to 6 amino acid segment of a reference sequence, GAQFSKTAAKGEAAAERPGEAAVA (SEQ ID NO:1), which amino acid segment is selected from the group consisting of SEQ ID NO: 176 to SEQ ID NO: 180, SEQ ID NO: 196 to SEQ ID NO: 199, SEQ ID NO: 217 and SEQ ID NO: 219;
wherein
(i) the C-terminal amino acid of said chemically modified peptide is chemically modified and the N-terminal amino acid of the peptide is alkylated or acylated at the N-terminal amino group; or
(ii) the C-terminal amino acid of said chemically modified peptide is chemically modified and the N-terminal amino acid of the peptide is not chemically modified; or
(iii) the N-terminal amino acid of said chemically modified peptide is alkylated or acylated at the N-terminal amino group and is not myristoylated and the C-terminal amino acid of the peptide is not chemically modified;
with the proviso that said chemically modified peptide contains no more than 6 amino acids; and
wherein said chemically modified peptide has a mucin hypersecretion-inhibiting effect when administered to a mammal in a mucin hypersecretion-inhibiting amount.
15. The modified peptide of claim 14 , wherein the N-terminal amino acid of the peptide is myristoylated at the N-terminal amino group.
16. The modified peptide of claim 14 , wherein the C-terminal amino acid of the peptide is amidated or esterified at the C-terminal carboxyl group.
17. A pharmaceutical composition comprising the peptide of claim 14 and a pharmaceutically acceptable carrier.
18. The pharmaceutical composition of claim 17 , wherein said composition is suitable for pulmonary administration.