Mimetics of interleukin-8 and methods of using them in the prevention, treatment, diagnosis, and ameliorization of symptoms of a disease

A composition comprising an IL-8 mimetic selected from a group consisting of SEQ ID NO:1642, variants a172 and a309, conservatively modified variants thereof, and prodrugs and codrugs thereof, wherein the IL-8 mimetic has the following structure:

• (SEQ ID NO:1642)
• RN-Asn-Trp-Val-Gln-Arg-Val-Val-Glu-Lys-Phe-Leu-
• Lys-Arg-Ala-Glu-Asn-RC;
• wherein,
• RN is selected from a group consisting of a hydrogen;
• an acetyl;
• an oligopeptide consisting of 3 to 19 amino acids;
• an oligopeptide consisting of 3 to 15 amino acids and a linker for connecting RN to the Asn1 residue of SEQ ID NO:1642;
• a diagnostic label;
• a glycosaminoglycan, a poly(ethylene glycol), or a derivative thereof, an N-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for aminopeptidases;
• and combinations thereof,
• RC is selected from a group consisting of a hydroxyl;
• an amido;
• an amino;
• a glycosaminoglycan, a poly(ethylene glycol), or a derivative thereof, a diagnostic label;
• a C-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for carboxypeptidases;
• and combinations thereof;
• and,
• the linker is selected from a group consisting of (a) any combination of four natural amino acids, and (b) any non-natural amino acid having the following structure:
• wherein, RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms that are optionally substituted with a hydroxyl, carboxyl, amino, amido, or imino group;
• or an aromatic group having from 5 to 7 members in the ring;
• and —(CH2)n—, wherein n is an integer ranging from 1 to 20.

A composition comprising an IL-8 mimetic selected from a group consisting of SEQ ID NO:36, variant a182, conservatively modified variants thereof, and prodrugs and codrugs thereof, wherein the IL-8 mimetic has the following structure:

• RN-Ser-Ala-Lys-Glu-Leu-Arg-Xaa1-Gln-Xaa2-Ile-Xaa4-Thr-Tyr-Ser-Lys-[linker]-Asn-Trp-Val-Gln-Arg-Val-Val-Glu-Lys-Phe-Leu-Lys-Arg-Ala-Glu-Asn-RC (SEQ ID NO:36);
• wherein,
• Xaa1, Xaa2, and Xaa4 are each independently selected from a group consisting of (a) any natural amino acid;
• and (b) any non-natural amino acid having the structure H2N—RL—COOH, where RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms, cycloalkyl amines, and fused cycloalkyl amines;
• RN is an N-terminal modifier comprising a component selected from a group consisting of a hydrogen, a poly(ethylene glycol) or derivative thereof, a diagnostic label, an acyl group, an acetyl group, and an N-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for aminopeptidases;
• RC is a C-terminal modifier comprising a component selected from a group consisting of a hydroxyl group, an amido group, an amino group, a poly(ethylene glycol) or derivative thereof, a diagnostic label, and a C-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for carboxypeptidases;
• and,
• the linker is selected from a group consisting of (a) any combination of four natural amino acids, and (b) any non-natural amino acid having the following structure:
• wherein, RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms that are optionally substituted with a hydroxyl, carboxyl, amino, amido, or imino group;
• or an aromatic group having from 5 to 7 members in the ring;
• and —(CH2)n—, wherein n is an integer ranging from 1 to 20.

A method of modulating an IL-8-mediated activity of a cell having an IL-8 receptor comprising binding the IL-8 receptor of the cell with an IL-8 mimetic selected from a group consisting of SEQ ID NO:1642, variants a172 and a309, conservatively modified variants thereof, and prodrugs and codrugs thereof, wherein the IL-8 mimetic has the following structure:

• (SEQ ID NO:1642)
• RN-Asn-Trp-Val-Gln-Arg-Val-Val-Glu-Lys-Phe-Leu-
• Lys-Arg-Ala-Glu-Asn-RC;
• wherein,
• RN is selected from a group consisting of a hydrogen;
• an acetyl;
• an oligopeptide consisting of 3 to 19 amino acids;
• an oligopeptide consisting of 3 to 15 amino acids and a linker for connecting RN to the Asn1 residue of SEQ ID NO:1642;
• a diagnostic label;
• a glycosaminoglycan, a poly(ethylene glycol), or a derivative thereof;
• an N-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for aminopeptidases;
• and combinations thereof;
• RC is selected from a group consisting of a hydroxyl;
• an amido;
• an amino;
• a glycosaminoglycan, a poly(ethylene glycol), or a derivative thereof;
• a diagnostic label;
• a C-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for carboxypeptidases;
• and combinations thereof;
• and,
• the linker is selected from a group consisting of (a) any combination of four natural amino acids, and (b) any non-natural amino acid having the following structure:
• wherein, RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms that are optionally substituted with a hydroxyl, carboxyl, amino, amido, or imino group;
• or an aromatic group having from 5 to 7 members in the ring;
• and —(CH2)n—, wherein n is an integer ranging from 1 to 20.

A method of increasing an IL-8-mediated activity of a cell having an IL-8 receptor comprising binding the IL-8 receptor of the cell with an IL-8 mimetic selected from a group consisting of SEQ ID NO:36, variant a182, conservatively modified variants thereof, and prodrugs and codrugs thereof, wherein the IL-8 mimetic has the following structure:

• RN-Ser-Ala-Lys-Glu-Leu-Arg-Xaa1-Gln-Xaa2-Ile-Xaa4-Thr-Tyr-Ser-Lys-[linker]-Asn-Trp-Val-Gln-Arg-Val-Val-Glu-Lys-Phe-Leu-Lys-Arg-Ala-Glu-Asn-RC (SEQ ID NO:36);
• wherein,
• Xaa1, Xaa2, and Xaa4 are each independently selected from a group consisting of (a) any natural amino acid;
• and (b) any non-natural amino acid having the structure H2N—RL—COOH, where RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms, cycloalkyl amines, and fused cycloalkyl amines;
• RN is an N-terminal modifier comprising a component selected from a group consisting of a hydrogen, a poly(ethylene glycol) or derivative thereof, a diagnostic label, an acyl group, an acetyl group, and an N-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for aminopeptidases;
• RC is a C-terminal modifier comprising a component selected from a group consisting of a hydroxyl group, an amido group, an amino group, a poly(ethylene glycol) or derivative thereof, a diagnostic label, and a C-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for carboxypeptidases;
• and,
• the linker is selected from a group consisting of (a) any combination of four natural amino acids, and (b) any non-natural amino acid having the following structure:
• wherein, RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms that are optionally substituted with a hydroxyl, carboxyl, amino, amido, or imino group;
• or an aromatic group having from 5 to 7 members in the ring;
• and —(CH2)n—, wherein n is an integer ranging from 1 to 20.

A method of increasing the number of hematopoietic cells circulating in the blood of a subject, wherein the method comprises administering an effective amount of a composition comprising an IL-8 mimetic selected from a group consisting of SEQ ID NO:36, variant a182, conservatively modified variants thereof, and prodrugs and codrugs thereof, wherein the IL-8 mimetic has the following structure:

• (SEQ ID NO:36)
• RN-Ser-Ala-Lys-Glu-Leu-Arg-Xaa1-Gln-Xaa2-Ile-Xaa4-
• Thr-Tyr-Ser-Lys-[linker]-Asn-Trp-Val-Gln-Arg-Val-
• Val-Glu-Lys-Phe-Leu-Lys-Arg-Ala-Glu-Asn-RC;
• wherein,
• Xaa1, Xaa2, and Xaa4 are each independently selected from a group consisting of (a) any natural amino acid;
• and (b) any non-natural amino acid having the structure H2N—RL—COOH, where RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms, cycloalkyl amines, and fused cycloalkyl amines;
• RN is an N-terminal modifier comprising a component selected from a group consisting of a hydrogen, a poly(ethylene glycol) or derivative thereof, a diagnostic label, an acyl group, an acetyl group, and an N-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for aminopeptidases;
• RC is a C-terminal modifier comprising a component selected from a group consisting of a hydroxyl group, an amido group, an amino group, a poly(ethylene glycol) or derivative thereof, a diagnostic label, and a C-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for carboxypeptidases;
• and,
• the linker is selected from a group consisting of (a) any combination of four natural amino acids, and (b) any non-natural amino acid having the following structure:
• wherein, RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms that are optionally substituted with a hydroxyl, carboxyl, amino, amido, or imino group;
• or an aromatic group having from 5 to 7 members in the ring;
• and —(CH2)n—, wherein n is an integer ranging from 1 to 20.

A method of treating a hematological disorder, wherein the method comprises administering an effective amount of a composition comprising an IL-8 mimetic selected from a group consisting of SEQ ID NO:36, variant a182, conservatively modified variants thereof, and prodrugs and codrugs thereof, wherein the IL-8 mimetic has the following structure:

• (SEQ ID NO:36)
• RN-Ser-Ala-Lys-Glu-Leu-Arg-Xaa1-Gln-Xaa2-Ile-Xaa4-
• Thr-Tyr-Ser-Lys-[linker]-Asn-Trp-Val-Gln-Arg-Val-
• Val-Glu-Lys-Phe-Leu-Lys-Arg-Ala-Glu-Asn-RC;
• wherein,
• Xaa1, Xaa2, and Xaa4 are each independently selected from a group consisting of (a) any natural amino acid;
• and (b) any non-natural amino acid having the structure H2N—RL—COOH, where RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms, cycloalkyl amines, and fused cycloalkyl amines;
• RN is an N-terminal modifier comprising a component selected from a group consisting of a hydrogen, a poly(ethylene glycol) or derivative thereof, a diagnostic label, an acyl group, an acetyl group, and an N-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for aminopeptidases;
• RC is a C-terminal modifier comprising a component selected from a group consisting of a hydroxyl group, an amido group, an amino group, a poly(ethylene glycol) or derivative thereof, a diagnostic label, and a C-terminal modifier capable of reducing the ability of the IL-8 mimetic to act as a substrate for carboxypeptidases;
• and,
• the linker is selected from a group consisting of (a) any combination of four natural amino acids, and (b) any non-natural amino acid having the following structure:
• wherein, RL is selected from a group consisting of saturated and unsaturated aliphatics and heteroaliphatics consisting of 20 or fewer carbon atoms that are optionally substituted with a hydroxyl, carboxyl, amino, amido, or imino group;
• or an aromatic group having from 5 to 7 members in the ring;
• and —(CH2)n—, wherein n is an integer ranging from 1 to 20.