Amphiphilic peptide compositions and analogues thereof

• US 5,294,605 A
• Filed: 07/08/1991
• Issued: 03/15/1994
• Est. Priority Date: 07/19/1990
• Status: Expired due to Term

• Current Assignee: The Scripps Research Institute
• Original Assignee: The Scripps Research Institute
• Inventors: Houghten, Richard A., Blondelle, Sylvie
• Primary Examiner(s): PRICKRIL, BENET
• Application Number:
  US07/725,331
• Time in Patent Office: 981 Days
• Field of Search: 514/12, 514/13, 530/327, 530/326, 530/325, 530/324
• US Class Current: 514/3.2
• 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: C07K 14/46 from vertebrates
• CPC Class Codes: C07K 7/08 having 12 to 20 amino acids gastrins C07K14/595; somatostatins C07K14/655; melanotropins C07K14/68

Abstract

A process for inhibiting growth of a target cell comprising administering to a host or to a target cell or virus a biologically active peptide which includes one of the following basic structures; R₁ -R₁ -R₂ -R₁ -R₁ -R₂ -R₂ -R₁ -R₁ -R₂ -R₂ -R₁ -R₂ -R₂ ; R₂ -R₁ -R₁ -R₂ -R₂ -R₁ -R₂ -R₂ -R₁ -R₁ -R₂ -R₂ -R₁ -R₁ ; or R₁ -R₂ -R₁ -R₁ -R₂ -R₂ -R₁ -R₁ -R₂ -R₂ -R₁ -R₂ -R₂ -R₁ -R₁ -R₂ -R₂ -R₁, wherein R₁ is a hydrophobic amino acid, and R₂ is a basic hydrophilic or neutral hydrophilic amino acid. A preferred peptide is of the structural formula:

(SEQ ID NO:3).

Substitution and deletion analogues of this peptide can be prepared that have increased biological activity. Such peptides can be employed as pharmaceuticals.

Claims

1. A process for inhibiting growth of a target cell comprising:

administering to a host a biologically active amphiphilic peptide, said peptide including the following structural formula;

space="preserve" listing-type="equation">R.sub.1 -R.sub.1 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2,

wherein -R₁ is a hydrophobic amino acid, and -R₂ is a basic hydrophilic or neutral hydrophilic amino acid, said peptide being administered in an amount effective to inhibit growth of a target cell in a host, wherein said hydrophobic amino acids are selected from the group consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, methionine sulfoxide, Val, Trp, and Tyr;

said basic hydrophilic amino acids are selected from the group consisting of Lys, Arg, His, orn, homoarginine 2,4-diaminobutyric acid, and p-aminophenylalanine; and

said neutral hydrophilic amino acids are selected from the group consisting of Asn, Gln, Ser, and Thr.

2. The process of claim 1 wherein said peptide has the following structural formula:

space="preserve" listing-type="equation">(SEQ ID NO;

1).

3. A process for inhibiting growth of a target cell comprising:

administering to a host a biologically active amphiphilic peptide, said peptide including the following structural formula;

space="preserve" listing-type="equation">R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1,

wherein R₁ is a hydrophobic amino acid, and R₂ is a basic hydrophilic or neutral hydrophilic amino acid, said peptide being administered in an amount effective to inhibit growth of a target cell in a host, wherein said hydrophobic amino acids are selected from the group consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, methionine sulfoxide, Val, Trp, and Tyr;

said basic hydrophilic amino acids are selected from the group consisting of Lys, Arg, His, orn, homoarginine 2,4-diaminobutyric acid, and p-aminophenylalanine; and

said neutral hydrophilic amino acids are selected from the group consisting of Asn, Gln, Ser, and Thr.

4. The process of claim 3 wherein said peptide has the following structural formula:

space="preserve" listing-type="equation">(SEQ ID NO;

2).

5. A biologically active amphiphilic peptide, said peptide being of the following structural formula:

space="preserve" listing-type="equation">R.sub.1 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1,

wherein R₁ is a hydrophobic amino acid, and R₂ is a basic hydrophilic or neutral hydrophilic amino acid, wherein said hydrophobic amino acids are selected from the group consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, methionine sulfoxide, Val, Trp, and Tyr;

said basic hydrophilic amino acids are selected from the group consisting of Lys, Arg, His, orn, homoarginine 2,4-diaminobutyric acid, and p-aminophenylalanine; and

said neutral hydrophilic amino acids are selected from the group consisting of Asn, Gln, Ser, and Thr.

6. The peptide of claim 5 wherein said peptide has the following structural formula:

space="preserve" listing-type="equation">(SEQ ID NO;

3).

7. A process for inhibiting growth of a target cell, comprising:

administering to a host a biologically active amphiphilic peptide, said peptide being of the following structural formula;

space="preserve" listing-type="equation">R.sub.1 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1,

wherein R₁ is a hydrophobic amino acid, and R₂ is a basic hydrophilic or neutral hydrophilic amino acid, said peptide being administered in an amount effective to inhibit growth of a target cell in a host, wherein said hydrophobic amino acids are selected from the group consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, methionine sulfoxide, Val, Trp, and Tyr;

said basic hydrophilic amino acids are selected from the group consisting of Lys, Arg, His, orn, homoarginine, 2,4-diaminobutyric acid, and p-aminophenylalanine; and

said neutral hydrophilic amino acids are selected from the group consisting of Asn, Gln, Ser, and Thr.

8. The process of claim 7 wherein said peptide has the following structural formula:

space="preserve" listing-type="equation">(SEQ ID NO;

3).

9. A compound, comprising:

an analogue of a peptide, said peptide being in an amide- or carboxy-terminated form, said peptide being represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide;

LeuLysLeuLeuLysLysLeuLeuLysLysLeuLysLysLeuLeuLysLysLeu 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 and wherein said peptide is substituted in at least one of positions 1, 3, 4 and 7-18 as follows;

space="preserve" listing-type="tabular">______________________________________ Residue No. Substituent ______________________________________ 1 Methionine sulfoxide, Lys, or Met 3 Methionine sulfoxide, Lys, or Met 4 Methionine sulfoxide, Lys, Met, His, Ser, or Arg 7 Methionine sulfoxide, Lys, or Met 8 Methionine sulfoxide, Lys, or Met 9 Methionine sulfoxide 10 Methionine sulfoxide 11 Methionine sulfoxide, Met, Ser, Lys, Arg, His, or Gly 12 Methionine sulfoxide 13 Methionine sulfoxide, or Met 14 Methionine sulfoxide, Lys, or Met 15 Methionine sulfoxide, Lys, or Met 16 Methionine sulfoxide 17 Methionine sulfoxide 18 Methionine sulfoxide, or Met ______________________________________

10. The compound of claim 9 wherein at least one of amino acid residues 1, 7, 8, 11, 14, 15, and 18 is substituted with methionine sulfoxide.

11. The compound of claim 9 wherein at least one of amino acid residues 1, 7, 8, 14, 15, and 18 is substituted with methionine sulfoxide.

12. The compound of claim 9 wherein at least one of amino acid residues 4, 7, 8, 11, and 14 is substituted with a lysine residue.

13. The compound of claim 9 wherein amino acid residues 4 is substituted with a methionine residue.

14. The compound of claim 9 wherein at least one of amino acid residues 4 and 11 is substituted with an arginine residue.

15. The compound of claim 9 wherein at least one of amino acid residues 4 and 11 is substituted with a histidine residue.

16. A process of inhibiting the growth of a microbe in a host, comprising:

administering to a host an effective anti-microbial amount of the compound of claim 9.

17. A process of inhibiting the growth of a tumor in a host, comprising:

administering to a host an effective anti-tumor amount of the compound of claim 9.

18. A compound comprising:

an analogue of a peptide, said peptide being in an amide- or carboxy-terminated form, said peptide being represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide;

LeuLysLeuLeuLysLysLeuLeuLysLysLeuLysLysLeuLeuLysLysLeu 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 and wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from said peptide.

19. The compound of claim 18 wherein at least one of amino acid residues 3, 7, 11, 14 or 18 is deleted from said peptide.

20. The compound of claim 18 wherein amino acid residues 1 through 3 are deleted from said peptide.

21. The compound of claim 18 wherein amino acid residues 1 through 4 are deleted from said peptide.

22. The compound of claim 18 wherein amino acid residues 1 through 6 are deleted from said peptide.

23. The compound of claim 18 wherein amino acid residues 1 through 7 are deleted from said peptide.

24. A process of inhibiting the growth of a microbe in a host, comprising:

administering to a host an effective anti-microbial amount of the compound of claim 18.

25. A process of inhibiting the growth of a virus in a host, comprising:

administering to a host an effective anti-viral amount of the compound of claim 18.

26. A process of inhibiting the growth of a tumor in a host, comprising:

administering to a host an effective anti-tumor amount of the compound of claim 18.

27. A biologically active amphiphilic peptide, said biologically active amphiphilic peptide including the following structural formula Y₁₀ :

space="preserve" listing-type="equation">R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1 -R.sub.2 -R.sub.2 -R.sub.1 -R.sub.1,

wherein R₁ is a hydrophobic amino acid, and R₂ is a basic hydrophilic or neutral hydrophilic amino acid, wherein said hydrophobic amino acids are selected from the group consisting of Ala, Cys, Phe, Gly, Ile, Leu, Met, methionine sulfoxide, Val, Trp, and Tyr;

said basic hydrophilic amino acids are selected from the group consisting of Lys, Arg, His, orn, homoarginine, 2,4-diaminobutyric acid, and p-aminophenylalanine; and

said neutral hydrophilic amino acids are selected from the group consisting of Asn, Gln, Ser, and Thr.

28. The peptide of claim 27 wherein said peptide includes the following structure:

Y₁₀ -Z₁₀, wherein Y₁₀ is the peptide structure of claim 27, and Z₁₀ is;

(i) R₂ ;

(ii) R₂ -R₁ ;

or

(iii) R₂ -R₁ -R₁.

29. The peptide of claim 28 wherein said peptide includes the following structural formula:

space="preserve" listing-type="equation">(SEQ ID NO;

4).

30. A process of inhibiting the growth of a microbe in a host, comprising:

administering to a host an effective anti-microbial amount of the peptide of claim 27.

31. A process of inhibiting the growth of a tumor in a host, comprising:

administering to a host an effective anti-tumor amount of the peptide of claim 27.