S-Alkylated Hepcidin Peptides and Methods of Making and Using Thereof

An S-alkylated hepcidin peptide comprising the following Structural Formula IA or IB

• A1-A2-A3-A4-A5-A6-A7-A8-A9-A10 IA
• A10-A9-A8-A7-A6-A5-A4-A3-A2-A1 IB
• wherein
• A1 is Asp, D-Asp, Glu, D-Glu, pyroglutamate, D-pyroglutamate, Gln, D-Gln, Asn, D-Asn, or an unnatural amino acid commonly used as a substitute thereof such as bhAsp, Ida, Ida(NHPal), and N-MeAsp, preferably Ida and N-MeAsp;
• A2 is Thr, D-Thr, Ser, D-Ser, Val, D-Val, Ile, D-Ile, Ala, D-Ala or an unnatural amino acid commonly used as a substitute thereof such as Tle, Inp, Chg, bhThr, and N-MeThr;
• A3 is His, D-His, Asn, D-Asn, Arg, D-Arg, or an unnatural amino acid commonly used as a substitute thereof such as L-His(π-Me), D-His(π-Me), L-His(τ-Me), or D-His(τ-Me);
• A4 is Phe, D-Phe, Leu, D-Leu, Ile, D-Ile, Trp, D-Trp, Tyr, D-Tyr, or an unnatural amino acid commonly used as a substitute thereof such as Phg, bhPhe, Dpa, Bip, 1Nal, 2Nal, bhDpa, Amc, PheF5, hPhe, Igl, or cyclohexylalanine, preferably Dpa;
• A5 is Pro, D-Pro, Ser, D-Ser, or an unnatural amino acid commonly used as a substitute thereof such as Oic, bhPro, trans-4-PhPro, cis-4-PhPro, cis-5-PhPro, and Idc, preferably bhPro;
• A6 is Arg, D-Arg, Ile, D-Ile, Leu, D-Leu, Thr, D-Thr, Lys, D-Lys, Val, D-Val, or an unnatural amino acid commonly used as a substitute thereof such as D-Nω,ω-dimethyl-arginine, L-Nω,ω-dimethyl-arginine, D-homoarginine, L-homoarginine, D-norarginine, L-norarginine, citrulline, a modified Arg wherein the guanidinium group is modified or substituted, Norleucine, norvaline, bhIle, Ach, N-MeArg, and N-Melle, preferably Arg;
• A7 is Cys, D-Cys, Ser, D-Ser, Ala, D-Ala, or an unnatural amino acid commonly used as a substitute thereof such as Cys(S-tBut), homoCys, Pen, (D)Pen, preferably S-tertiary butyl-cysteine, Cys(S-S-Pal), Cys(S-S-cysteamine-Pal), Cys(S-S-Cys-NHPal), and Cys(S-S-Cys);
• A8 is Arg, D-Arg, Ile, D-Ile, Leu, D-Leu, Thr, D-Thr, Lys, D-Lys, Val, D-Val, or an unnatural amino acid commonly used as a substitute thereof such as D-Nω,ω-dimethyl-arginine, L-Nω,ω-dimethyl-arginine, D-homoarginine, L-homoarginine, D-norarginine, L-norarginine, citrulline, a modified Arg wherein the guanidinium group is modified or substituted, Norleucine, norvaline, bhIle, Ach, N-MeArg, and N-Melle, preferably Arg;
• A9 is Phe, D-Phe, Leu, D-Leu, Ile, D-Ile, Tyr, D-Tyr, Trp, D-Trp, Phe-Ra, D-Phe-Ra, Dpa-Ra, D-Dpa-Ra, Trp-Ra, bhPhe-Ra, or an unnatural amino acid commonly used as a substitute thereof such as PheF5, N-MePhe, benzylamide, 2-aminoindane, bhPhe, Dpa, Bip, 1Nal, 2Nal, bhDpa, and cyclohexylalanine, which may or may not have Ra linked thereto, preferably bhPhe and bhPhe-Ra, wherein Ra is palmitoyl-PEG-, wherein PEG is PEG11 or miniPEG3, palmitoyl-PEG-PEG, wherein PEG is PEG11 or miniPEG3, butanoyl (C4)-PEG11-, octanoyl (C8, Caprylic)-PEG11-, palmitoyl (C16)-PEG11-, or tetracosanoyl (C24, Lignoceric)-PEG11-;
• and
• A10 is Cys, D-Cys, Ser, D-Ser, Ala, D-Ala, or an unnatural amino acid such as Ida, Ida(NHPal)Ahx, and Ida(NBzl2)Ahx;
• and
• at least one of the amino acid residues A1 to A10 has Structural Formula A:
• wherein
• n is 1 or 2 and one or more of the hydrogens bonded to the Cn atom(s) may be substituted with a (C1-C3)alkyl,
• X1 and X2 are each independently selected from the group consisting of H, alkyl, alkoxy, alkoxycarbonyl, cycloalkyl, aryl, heteroaryl, heterocycloalkyl, acyl, sulfonyl, alkyl sulfonyl, alkylamino, alkylaminocarbonyl, dialkylaninocarbonyl, carboxyl, and carbamoyl;
• wherein the carboxy-terminal amino acid is in amide or carboxy-form;
• and
• wherein A1, A1 to A2, A10, or a combination thereof are optionally absent.