Mini-hepcidin peptides and methods of using thereof

• US 8,435,941 B2
• Filed: 12/04/2009
• Issued: 05/07/2013
• Est. Priority Date: 12/05/2008
• Status: Expired due to Fees

• Current Assignee: Regents of the University of California (University of California)
• Original Assignee: Regents of the University of California (University of California)
• Inventors: Ganz, Tomas, Nemeth, Elizabeta, Preza, Gloria, Ruchala, Piotr Pawel
• Primary Examiner(s): Tsang, Cecilia J
• Assistant Examiner(s): REYNOLDS, FRED H
• Application Number:
  US13/131,792
• Publication Number:
  US 20120040894A1
• Time in Patent Office: 1,250 Days
• Field of Search: None
• US Class Current: 514/5.4
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 3/00 Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: C07K 14/575 Hormones derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695
• CPC Class Codes: C07K 7/06 having 5 to 11 amino acids

Abstract

Disclosed herein are peptides which exhibit hepcidin activity and methods of making and using thereof.

Claims

1. An isolated peptide consisting of the following structural formula

A1-A2-A3-A4-A5-A6-A7-A8-A9-A10

wherein

A1 is Asp, Glu, pyroglutamate, Gln, Asn, D-Asp, D-Glu, D-pyroglutamate, D-Gln, D-Asn, bhAsp, Ida, or N-MeAsp, Ala, D-Ala, Cys, D-Cys, Phe, D-Phe, Asp or D-Asp, or Dpa or (D)Dpa;

where if Al is Asp or D-Asp, A2 is Cys or D-Cys, if A1 is Phe or D-Phe the n-terminus is optionally attached to a PEG molecule linked to chenodeoxvcholate, ursodeoxvcholate, or palmitoyl, or if A1 is Dpa or (D)Dpa is attached at the n-terminus to palmitoyl,

A2 is Thr, Ser, Val, Ala, D-Thr, D-Ser, D-Val, Tle, Inp, Chg, bhThr, N-MeThr, D-Ala, Cys, D-Cys, Pro, D-Pro, Gly, or D-Gly;

A3 is His, D-His, Dpa, (D)Dpa, or 2-aminoindane;

A4 is Phe, D-Phe, bhPhe, Dpa, Bip, lNal, bhDpa, Amc, PheF5, hPhe, Igl, or cyclohexylalanine;

A5 is Pro, D-Pro, Oic, bhPro, trans-4-PhPro, cis-4-PhPro, cis-5-PhPro, or Idc;

A6 is Ile, D-Ile, Phg, Chg, Amc, bhIle, Ach, or MeIle;

A7 is Cys, D-Cys, Cys(S-tBut), homoC, Pen, or (D)Pen;

A8 is Ile, D-Ile, Chg, Dpa, bhIle, Ach, or MeIle;

A9 is Phe, Leu, Ile, Tyr, D-Phe, D-Leu, D-He, PheF5, N-MePhe, benzylamide, bhPhe, Dpa, Bip, 1Nal, bhDpa, cyclohexylalanine, Asp, D-Asp, or cysteamide,

wherein Phe or D-Phe are optionally linked at the n-terminus to RA, Asp or D-Asp are optionally linked at the n-terminus to RB, bhPhe is linked to RC,

wherein RA is -CONH-CH2-CH2-S-, or D-Pro linked to Pro-Lys or Pro-Arg, or bhPro linked to Pro linked to Pro-Lys or Pro-Arg, or D-Pro linked to bhPro Lys or bhPro-Arg,

wherein RB is -PEG 11-GYIPEAPRDGQAYVRKDGEWVLLSTFL, or -(PEG

     11)-(GPHyp)₁₀,

wherein RC is -D-Pro linked to Pro-Lys or ProArg, or -D-Pro linked to bhPro-Lys or bhPro-Arg; and

A10 is Cys, Ser, Ala, D-Cys, D-Ser, or D-Ala;

wherein the carboxy-terminal amino acid is in amide or carboxy- form;

wherein at least one sulfhydryl amino acid is present as one of the amino acids in the sequence;

wherein A1, A2, A1 to A2, A10, A9 to A10, or a combination thereof are optionally absent

wherein

bhAsp is 3-aminopentanedioic acid,

Ida is 2,2′

-azanediyldiacetic acid,

N-MeAsp is (methylamino)pentanedioic acid,

Tle is L-tert-leucine,

Inp is isonipecotic acid,

Chg is L-α

-cyclohexylglycine,

N-MeThr is (2S)-3-hydroxy-2-(methylamino)butanoic acid,

Dpa is 3,3-diphenyl-L-alanine,

(D)Dpa is 3,3-diphenyl-D-alanine,

bhPhe is (S)-2-amino-4-phenylbutanoic acid,

Bip is L-biphenylalanine,

1Nal is (1-naphthyl)-L-alanine,

bhDpa is (S)-3-Amino-4,4-diphenylbutanoic acid,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

PheF5 is (S)-2-amino-3-(perfluorophenyl)propanoic acid,

hPhe is (S)-2-amino-4-phenylbutanoic acid,

Igl is (S)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acid,

Oic is octahydroindole-2-carboxylic acid,

bhPro is L-β

-homoproline,

trans-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-5-PhPro is (2S,5R)-5-phenylpyrrolidine-2-carboxylic acid,

Idc is (R)-2-methylindoline,

Phg is L-phenylglycine,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

bhIle is (3R)-3-amino-4-methylhexanoic acid,

Ach is 1-aminocyclohexane-1-carboxylic acid,

MeIle is (3R)-4-methyl-3-(methylamino)hexanoic acid,

Cys(S-tBut) is S-t-Butylthio-L-cysteine,

homoC is L-homocysteine,

Pen is L-Penicillamine, and

(D)Pen is D-Penicillamine GPHyp is Gly-Pro-HydroxyPro.

2. The peptide of claim 1, wherein A1 is Asp, A2 is Thr, A3 is His, A4 is Phe, A5 is Pro, A6 is Ile, A7 is Cys, D-Cys, Cys(S-tBut), homoC, Pen, or (D)Pen, A8 is Ile, A9 is Phe in amide form, and A10 is absent.

3. The peptide of claim 1, wherein A1 and A2 are absent, A3 is His, A4 is Phe, A5 is Pro, A6 is Ile, A7 is Cys D-Cys, Cys(S-tBut), homoC, Pen, or (D)Pen, A8 is Ile in amide form, and A9and A10 are absent.

4. The peptide of claim 1, wherein A1 and A2 are absent, A3 is His, A4 is Phe, A5 is Pro, A6 is Ile, A7 is Cys D-Cys, Cys(S-tBut), homoC, Pen, or (D)Pen, and A8 to A10 are absent, where the C-terminus is in amide form.

5. The peptide of claim 1, wherein the peptide is a cyclic peptide.

6. The peptide of according to claim 1, wherein the sequence is retroinverted such that A1 is the C-terminus and A10 is the N-terminus.

9. The peptide according to claim 1, wherein the peptide exhibits hepcidin activity.

10. The peptide according to claim 1, wherein the peptide binds ferroportin.

11. A composition which comprises at least one peptide according to claim 1.

12. A method of binding a ferroportin or inducing ferroportin internalization and degradation which comprises contacting the ferroportin with at least one peptide according to claim 1.

13. A method of treating a disease of iron metabolism in a subject which comprises administering at least one peptide according to claim 1 to the subject.

14. The method of claim 13, wherein the disease of iron metabolism is an iron overload disease.

15. A kit comprising at least one peptide according to claim 1 packaged together with a reagent, a device, instructional material, or a combination thereof.

16. A complex comprising at least one peptide according to claim 1 bound to a ferroportin or an antibody.

18. The isolated peptide of claim 1, wherein the peptide binds to ferroportin with an EC₅₀ of about 1000 nM or less.

7. An isolated peptide consisting of the following structural formula

A1-A2-A3-A4-A5-A6-A7-A8-A9-A10

wherein

A1 is Asp, Glu, pyroglutamate, Gln, Asn, D-Asp, D-Glu, D-pyroglutamate, D-Gln, D-Asn, bhAsp, Ida, or N-MeAsp, Ala, D-Ala, Cys, D-Cys, Phe, D-Phe, Asp or D-Asp, or Dpa or (D)Dpa;

where if A1 is Asp or D-Asp, A2 is Cys or D-Cys, if A1 is Phe or D-Phe the n-terminus is optionally attached to a PEG molecule linked to chenodeoxvcholate, ursodeoxvcholate, or palmitoyl, or if A1 is Dpa or (D)Dpa is attached at the n-terminus to palmitoyl,

A2 is Thr, Ser, Val, Ala, D-Thr, D-Ser, D-Val, Tle, Inp, Chg, N-MeThr, D-Ala, Cys, D-Cys, Pro, D-Pro, Gly, or D-Gly;

A3 is His, D-His, Dpa, (D)Dpa, or 2-aminoindane;

A4 is Phe, D-Phe, bhPhe, Dpa, Bip, lNal, bhDpa, Amc, PheF5, hPhe, Igl, or cyclohexylalanine;

A5 is Pro, D-Pro, Oic, bhPro, trans-4-PhPro, cis-4-PhPro, cis-5-PhPro, or Idc;

A6 is Ile, D-Ile, Phg, Chg, Amc, bhIle, Ach, or MeIle;

A7 is Cys, D-Cys, Cys(S-tBut), homoC, Pen, (D)Pen, or Dap(AcBr);

A8 is Ile, D-Ile, Chg, Dpa, bhIle, Ach, or MeIle;

A9 is Phe, Leu, Ile, Tyr, D-Phe, D-Leu, D-He, PheF5, N-MePhe, benzylamide, bhPhe, Dpa, Bip, 1Nal, bhDpa, cyclohexylalanine, Asp, D-Asp, or cysteamide,

wherein Phe or D-Phe are optionally linked at the n-terminus to RA, Asp or D-Asp are optionally linked at the n-terminus to RB, bhPhe is linked to RC,

wherein RA is -CONH-CH2-CH2-S-, or D-Pro linked to Pro-Lys or Pro-Arg, or bhPro linked to Pro linked to Pro-Lys or Pro-Arg, or D-Pro linked to bhPro Lys or bhPro-Arg,

wherein RB is -PEG 11-GYIPEAPRDGQAYVRKDGEWVLLSTFL, or -(PEG

     11)-(GPHyp)₁₀,

wherein RC is -D-Pro linked to Pro-Lys or ProArg, or -D-Pro linked to bhPro-Lys or bhPro-Arg; and

A10 is Cys, Ser, Ala, D-Cys, D-Ser, or D-Ala;

wherein the carboxy-terminal amino acid is in amide or carboxy- form;

wherein at least one sulfhydryl amino acid is present as one of the amino acids in the sequence; and

wherein A1, A2, A1 to A2, A10, A9 to A10, or a combination thereof are optionally absent,

wherein the peptide has -CONH₂-CH₂-CH₂-S, Chenodeoxycholate-(PEG11)-, Ursodeoxycholate-(PEG11)-, Palmitoyl-(PEG11)-, 2(Palmitoyl)-diaminopropionic acid-(PEG11)-, -PEG11-GYIPEAPRDGQAYVRKDGEWVLLSTFL, -(PEG11)-(Gly-Pro-hydroxyproline)10, -(D)P-PK, -(D)P-PR, -bhProPK, -bhProPR, (D)P-bhProK, or -(D)P-bhProR at the N-terminus, C-terminus, or both,

wherein

bhAsp is 3-aminopentanedioic acid,

Ida is 2,2′

-azanediyldiacetic acid,

N-MeAsp is (methylamino)pentanedioic acid,

Tle is L-tert-leucine,

Inp is isonipecotic acid,

Chg is L-a-cyclohexylglycine,

N-MeThr is (2S)-3-hydroxy-2-(methylamino)butanoic acid,

Dpa is 3,3-diphenyl-L-alanine,

(D)Dpa is 3,3-diphenyl-D-alanine,

bhPhe is (S)-2-amino-4-phenylbutanoic acid,

Bip is L-biphenylalanine,

1Nal is (1-naphthyl)-L-alanine,

bhDpa is (S)-3-Amino-4,4-diphenylbutanoic acid,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

PheF5 is (S)-2-amino-3-(perfluorophenyl)propanoic acid,

hPhe is (S)-2-amino-4-phenylbutanoic acid,

Igl is (S)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acid,

Oic is octahydroindole-2-carboxylic acid,

bhPro is L-β

-homoproline,

trans-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-5-PhPro is (2S,5R)-5-phenylpyrrolidine-2-carboxylic acid,

Idc is (R)-2-methylindoline,

Phg is L-phenylglycine,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

bhIle is (3R)-3-amino-4-methylhexanoic acid,

Ach is 1-aminocyclohexane-1-carboxylic acid,

MeIle is (3R)-4-methyl-3-(methylamino)hexanoic acid,

Cys(S-tBut) is S-t-Butylthio-L-cysteine,

homoC is L-homocysteine,

Pen is L-Penicillamine, and

(D)Pen is D-Penicillamine GPHyp is Gly-Pro-HydroxyPro.

8. A peptide selected from the group consisting of

H-F-P-I-C-I,

H-F-P-I-C-I-F,

D-T-H-F-P-I-C-I-D-T-H-F-P-I-C-I-F,

D-T-H-F-P-I-A-I-F-C,

D-T-H-A-P-I-C-I-F,

D-T-H-A-P-I-CS-S-tBut-I-F,

D-T-H-F-P-I-C-I-F,

D-T-H-F-P-I-homoC-I-F,

D-T-H-F-P-I-Pen-I-F,

D-T-H-F-P-I-(D)Pen-I-F,

C-D-T-H-F-P-I-C-I-F,

D-Tle-H-Phg-Oic-Chg-C-Chg-F,

D-Tle-H-P-Oic-Chg-C-Chg-F,

(D)F-(D)I-(D)C-(D)I-(D)P-(D)F-(D)H-(D)T-(D)D,

(D)F-(D)I-(D)C-(D)I-(D)P-(D)F-(D)H,

R2-(D)F-(D)I-(D)C-(D)I-(D)P-(D)F-(D)H-(D)T-(D)D,

R3-(D)F-(D)I-(D)C-(D)I-(D)P-(D)F-(D)H-(D)T-(D)D,

(D)F-(D)I-(D)C-(D)I-(D)P-(D)F-(D)H-(D)T-(D)D-R6,

R4-(D)F-(D)I-(D)C-(D)I-(D)P-(D)F-(D)H-(D)T-(D)D,

R5-(D)F-(D)I-(D)C-(D)I-(D)P-(D)F-(D)H-(D)T-(D)D,

D-T-H-bhPhe-P-I-C-I-F,

D-T-H-Dpa-P-I-C-I-F,

D-T-H-Bip-P-I-C-I-F,

D-T-H-1Nal-P-I-C-I-F,

D-T-H-bhDpa-P-I-C-I-F,

D-T-H-F-P-I-C-I-bhPhe,

D-T-H-F-P-I-C-I-Dpa,

D-T-H-F-P-I-C-I-Bip,

D-T-H-F-P-I-C-I-1Nal,

D-T-H-F-P-I-C-I-bhDpa,

D-T-H-Dpa-P-I-C-I-Dpa,

D-Dpa-P-I-C-I-F,

D-Dpa-P-I-C-I-Dpa,

D-T-H-Dpa-P-R-C-R-Dpa,

D-T-H-Dpa-P-(D)R-C-(D)R-Dpa,

D-T-H-Dpa-Oic-I-C-I-F,

D-T-H-Dpa-Oic-I-C-I-Dpa,

D-T-H-Dpa-P-C-C-C-Dpa,

D-T-H-F-P-I-C-I-F-R8,

D-T-H-F-P-I-C-I-F-R9,

D-T-H-F-P-I-C-I-F-R10,

D-T-H-F-P-I-C-I-F-R11,

D-T-H-F-P-I-C-I-F-R12,

D-T-H-F-P-I-C-I-F-R13,

D-T-H-F-P-I-C-I-bhPhe-R8,

D-T-H-F-P-I-C-I-bhPhe-R9,

D-T-H-F-P-I-C-I-bhPhe-R12,

D-T-H-F-P-I-C-I-bhPhe-R13,

C-Inp-(D)Dpa-Amc-R-Amc-Inp-Dpa-Cysteamide,

C-P-(D)Dpa-Amc-R-Amc-Inp-Dpa-Cysteamide,

C-(D)P-(D)Dpa-Amc-R -Amc-Inp-Dpa-Cysteamide, and

C-G-(D)Dpa-Amc-R-Amc-Inp-Dpa-Cysteamide,

wherein R1 =-CONH₂-CH₂-CH₂-S, R2 =Chenodeoxycholate-(PEG11)-, R3 =Ursodeoxycholate-(PEG11)-, R4=Palmitoyl-(PEG11)-, R5=2(Palmitoyl)- diaminopropionic acid-(PEG11)- , R6=-PEG11 -GYIPEAPRDGQAYVRKDGEWVLLSTFL, R7=-(PEG11)- (Gly-Pro-hydroxyproline)10,R8=-(D)P-PK, R9=-(D)P-PR, R10=-bhProPK, R11=-bhProPR, R12=-(D)P-bhProK, and R13=-(D)P-bhProR,

wherein

bhAsp is 3-aminopentanedioic acid,

Ida is 2,2′

-azanediyldiacetic acid,

N-MeAsp is (methylamino)pentanedioic acid,

Tle is L-tert-leucine,

Inp is isonipecotic acid,

Chg is L-α

-cyclohexylglycine,

N-MeThr is (2S)-3-hydroxy-2-(methylamino)butanoic acid,

Dpa is 3,3-diphenyl-L-alanine,

(D)Dpa is 3,3-diphenyl-D-alanine,

bhPhe is (S)-2-amino-4-phenylbutanoic acid,

Bip is L-biphenylalanine,

1Nal is (1-naphthyl)-L-alanine,

bhDpa is (S)-3-Amino-4,4-diphenylbutanoic acid,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

PheF5 is (S)-2-amino-3-(perfluorophenyl)propanoic acid,

hPhe is (S)-2-amino-4-phenylbutanoic acid,

Igl is (S)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acid,

Oic is octahydroindole-2-carboxylic acid,

bhPro is L-β

-homoproline,

trans-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-5-PhPro is (2S,5R)-5-phenylpyrrolidine-2-carboxylic acid,

Idc is (R)-2-methylindoline,

Phg is L-phenylglycine,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

bhIle is (3R)-3-amino-4-methylhexanoic acid,

Ach is 1-aminocyclohexane-1-carboxylic acid,

MeIle is (3R)-4-methyl-3-(methylamino)hexanoic acid,

Cys(S-tBut) is S-t-Butylthio-L-cysteine,

homoC is L-homocysteine,

Pen is L-Penicillamine, and

(D)Pen is D-Penicillamine.

17. An isolated peptide consisting of the following structural formula

A1-A2-A3-A4-A5-A6-A7-A8-A9-A10

wherein

A1 is Asp, Glu, pyroglutamate, Gln, Asn, D-Asp, D-Glu, D-pyroglutamate, D-Gln, D-Asn, bhAsp, Ida, or N-MeAsp, Ala, D-Ala, Cys, D-Cys, Phe, D-Phe, Asp or D-Asp, or Dpa or (D)Dpa;

where if A1 is Asp or D-Asp, A2 is Cys or D-Cys, if A1 is Phe or D-Phe the n-terminus is optionally attached to a PEG molecule linked to chenodeoxvcholate, ursodeoxvcholate, or palmitoyl, or if A1 is Dpa or (D)Dpa is attached at the n-terminus to palmitoyl,

A2 is Thr, Ser, Val, Ala, D-Thr, D-Ser, D-Val, Tle, Inp, Chg, N-MeThr, D-Ala, Cys, D-Cys, Pro, D-Pro, Gly, or D-Gly;

A3 is His;

A4 is Phe;

A5 is Pro;

A6 is Ile;

A7 is Cys, D-Cys, Cys(S-tBut), or homoC;

A8 is Ile;

A9 is Phe, Leu, Ile, Tyr, D-Phe, D-Leu, D-He, PheF5, N-MePhe, benzylamide, bhPhe, Dpa, Bip, 1Nal, bhDpa, cyclohexylalanine, Asp, D-Asp, or cysteamide,

wherein Phe or D-Phe are optionally linked at the n-terminus to RA, Asp or D-Asp are optionally linked at the n-terminus to RB, bhPhe is linked to RC,

wherein RA is -CONH-CH2-CH2-S-, or D-Pro linked to Pro-Lys or Pro-Arg, or bhPro linked to Pro linked to Pro-Lys or Pro-Arg, or D-Pro linked to bhPro Lys or bhPro-Arg,

wherein RB is -PEG 11-GYIPEAPRDGQAYVRKDGEWVLLSTFL, or -(PEG

     11)-(GPHyp)₁₀,

wherein RC is -D-Pro linked to Pro-Lys or ProArg, or -D-Pro linked to bhPro-Lys or bhPro-Arg; and

A10 is Cys, Ser, Ala, D-Cys, D-Ser, or D-Ala;

wherein the carboxy-terminal amino acid is in amide or carboxy- form;

wherein at least one sulfhydryl amino acid is present as one of the amino acids in the sequence; and

wherein A1, A2, A1 to A2, A10, A9 to A10, or a combination thereof are optionally absent

wherein

bhAsp is 3-aminopentanedioic acid,

Ida is 2,2′

-azanediyldiacetic acid,

N-MeAsp is (methylamino)pentanedioic acid,

Tle is L-tert-leucine,

Inp is isonipecotic acid,

Chg is L-α

-cyclohexylglycine,

N-MeThr is (2S)-3-hydroxy-2-(methylamino)butanoic acid,

Dpa is 3,3-diphenyl-L-alanine,

(D)Dpa is 3,3-diphenyl-D-alanine,

bhPhe is (S)-2-amino-4-phenylbutanoic acid,

Bip is L-biphenylalanine,

1Nal is (1-naphthyl)-L-alanine,

bhDpa is (S)-3-Amino-4,4-diphenylbutanoic acid,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

PheF5 is (S)-2-amino-3-(perfluorophenyl)propanoic acid,

hPhe is (S)-2-amino-4-phenylbutanoic acid,

Igl is (S)-2-amino-2-(2,3-dihydro-1H-inden-2-yl)acetic acid,

Oic is octahydroindole-2-carboxylic acid,

bhPro is L-β

-homoproline,

trans-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-4-PhPro is (2S,4S)-4-phenylpyrrolidine-2-carboxylic acid,

cis-5-PhPro is (2S,5R)-5-phenylpyrrolidine-2-carboxylic acid,

Idc is (R)-2-methylindoline,

Phg is L-phenylglycine,

Amc is 4-(aminomethyl)cyclohexane carboxylic acid,

bhIle is (3R)-3-amino-4-methylhexanoic acid,

Ach is 1-aminocyclohexane-l-carboxylic acid,

MeIle is (3R)-4-methyl-3-(methylamino)hexanoic acid,

Cys(S-tBut) is S-t-Butylthio-L-cysteine,

homoC is L-homocysteine,

Pen is L-Penicillamine, and

(D)Pen is D-Penicillamine.