WO1994012206A1 - Treatment of dermatological malignancies with biologically active peptides - Google Patents

Abstract

A process for treating a dermatological malignancy, such as melannoma, in a host which comprises administering to the host at least one biologically active amphiphilic peptide or protein. The peptide or protein may be administered intralesionally, whereby the peptide or protein may inhibit, prevent, or destroy the growth of the dermatological malignancy.

Description

TREATMENT OF DERMATOLOGICAL MALIGNANCIES

WITΗ BIOLOGICALLY ACTIVE PEPTIDES

This invention relates to the treatment of rermatological malignancies, such as melanoma. More particularly, this invention relates to the treatment of iermatological malignancies by administering a biologically active peptide or protein.

In accordance with an aspect of the present invention, there is provided a process for treating a dernatological malignancy in a host comprising administering to a host at least one biologically active amphiphilic peptide or protein. The peptide or protein is an ion channel-forming peptide or protein. The peptide or protein is administered in an amount effective to treat a dermatological malignancy in a host.

The term "treating a dertnatological malignancy" as used herein means that the peptide or protein prevents, inhibits, or destroys the growth of a dermatological malignancy or skin cancer, and/or reduces the size of or eliminates the dermatological malignancy.

An ion channel-forming peptide or protein or ionophore is a peptide or protein which increases the permeability for ions across a natural or synthetic lipid membrane. B. Christensen, et al., PNAS, Vol. 85, pgs. 5072-5076 (July 1988) describes methodology which indicates whether or not a peptide has ion channel-forming properties and is therefore an ionophore. As used herein an ion channel-forming peptide or ion channel-forming protein is a peptide or protein which has ion channel-forming properties as determined by the method of Christensen, et al.

An amphiphilic peptide or protein is a peptide or protein which includes both hydrophobic and hydrophilic peptide or protein regions.

The ion channel-forming peptides employed in the present invention are generally water soluble to a concentration of at least 20 mg/ml at neutral pH in water. In addition, the structure of such peptide provides for flexibility of the peptide molecule. Such peptides are capable of forming an alpha-helix. When the peptide is placed in water, it does not assume an amphiphilic structure. When the peptide encounters an oily surface or membrane, the peptide chain folds upon itself into a rodlike structure.

In general, such peptides have at least 7 amino acids, and in many cases have at least 20 amino acids. In most cases, such peptides do not have in excess of 40 amino acids.

As stated hereinabove, the peptides or proteins are administered in an amount effective to treat a dermatological malignancy in a host. The peptides or proteins may be administered to a host in vivo, such as, for example, through systemic administration. In one embodiment, the peptides or proteins may be administered intralesionally; i.e., the peptide or protein is injected directly into the dermatological malignancy. The peptide or protein may be administered in an amount of from about 50 μg per injection to about 100 mg per injection, preferably such that peptide dosages are from about 1 mg/kg to about 5 mg/kg body weight. The peptides or proteins may also be administered intravenously or intraperitoneally. The peptide or protein may be administered in multiple doses. In one embodiment, the peptide or protein may be administered two times a week for a period of 4 weeks.

In another embodiment, the peptide or protein may be administered topically in an amount of from about 1 mg/kg to about 5 mg/kg of body weight.

The peptides or proteins are administered in combination with an acceptable pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution. The peptides or proteins may also be used in combination with adjuvants, protease inhibitors, or compatible drugs.

Dermatological malignancies which may be treated include, but are not limited to, melanoma, basal cell carcinoma, and squamous cell carcinoma. The dermatological malignancy may be metastatic or non-metastatic. In one embodiment, the peptide is a basic (positively charged) polypeptide having at least sixteen amino acids wherein the polypeptide includes at least eight hydrophobic amino acids and at least eight hydrophilic amino acids. Still more particularly, the hydrophobic amino acids are in groups of two adjacent amino acids, and each group of two hydrophobic amino acids is spaced from another group of two hydrophobic amino acids by at least one amino acid other than a hydrophobic amino acid (preferably at least two amino acids) and generally by no greater than four amino acids, and the amino acids between pairs of hydrophobic amino acids may or may not be hydrophilic.

The hydrophilic amino acids are generally also in groups of two adjacent amino acids in which at least one of the two amino acids is a basic hydrophilic amino acid, with such groups of two hydrophilic amino acids being spaced from each other by at least one amino acid other than a hydrophilic amino acid (preferably at least two amino acids) and generally no greater than four amino acids, and the amino acids between pairs of hydrophilic amino acids may or may not be hydrophobic.

In accordance with a particularly preferred embodiment, the polypeptide comprises a chain of at least four groups of amino acids, with each group consisting of four amino acids. Two of the four amino acids in each group are hydrophobic amino acids, and two of the four amino acids in each group are hydrophilic, with at least one of the hydrophilic amino acids in each group being a basic hydrophilic amino acid and the other being a basic or neutral hydrophilic amino acid.

The hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, lle, Leu, Met, Pro, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha). The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, Thr and homoserine (Hse). The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2, 4-diaminobutyric acid (Dbu), and p-aminophenylalanine.

Each of the groups of four amino acids may be of the sequence ABCD, BCDA, CDAB, or DABC, wherein A and B are each hydrophobic amino acids and may be the same or different, one of C or D is a basic hydrophilic amino acid, and the other of C or D is a basic or neutral hydrophilic amino acid and may be the same or different. In one embodiment, the polypeptide chain may comprise 5 or 6 groups of this sequence. In each group, each of A, B, C and D may be the same in some or all of the groups or may be different in some or all of the groups.

The polypeptide chain preferably has at least 20 amino acids, and no greater than 50 amino acids. It is to be understood, however, that the polypeptide does not have to consist entirely of the groups described above. The polypeptide may have amino acids extending from either or both ends of the noted groups forming the polypeptide chain and/or there may be amino acids between one or more of the at least four groups and still remain within the scope of the invention.

The groups of amino acids may be repeating groups of amino acids, or the amino acids in the various groups may vary provided that in each group of the at least four groups of amino acids there are two hydrophobic and two hydrophilic amino acids as hereinabove noted.

Thus the biologically active polypeptide may comprise a chain including at least four groups of amino acids, each containing four amino acids. Two of the four amino acids in each group are hydrophobic, at least one amino acid is basic hydrophilic, and the remaining one is basic or neutral hydrophilic, with the polypeptide chain preferably having at least 20 amino acids but no greater than 50 amino acids.

In one embodiment, each of the at least four groups of amino acids which are in the peptide chain is of the sequence A-B-C-D, B-C-D-A, C-D-A-B or D-A-B-C wherein A and B are hydrophobic amino acids, one of C or D is a basic hydrophilic amino acid, and the other of C or D is basic or neutral hydrophilic amino acid. The resulting polypeptide chain, therefore, may have one of the following sequences:

(X₁)_a (A-B-C-D)_n(Y₁)_b (X₂)_a(B-C-D-A)_n(Y₂)_b

(X₃)_a(C-D-A-B)_n(Y₃)_b

(X₄)_a(D-A-B-C)_n(Y₄)_b

wherein X₁ is D; C-D- or B-C-D-, Y₁ is -A or -A-B or

-A-B-C

X₂ is A-, D-A- or C-D-A-

Y is -B, -B-C or B-C-D

X₃is B-, A-B-, D-A-B-

Y₃ is -C, -C-D, -C-D-A

X₄ is C-, B-C-, A-B-C-

Y_A is -D, -D-A, -D-A-B

a is 0 or 1; b is 0 or 1

and n is at least 4.

It is to be understood that the peptide chain may include Amino acids between the hereinabove noted groups of four amino acids provided that the spacing between such groups and the charge on the amino acids does not change the characteristics of the peptide chain which provide amphiphilicity and a positive charge and do not adversely affect the folding characteristics of the chain to that which is significantly different from one in which the hereinabove noted group of four amino acids are not spaced from each other.

As representative examples of such peptides, there may be mentioned.

I Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-

Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys (SEQ I NO: 1)

II Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser- Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe- Ser-Lys. (SEQ ID NO: 2)

III Pho-Ser-Lys-Ala-Phe-Ser- Lys-Ala-Phe-Ser-Lys-Ala- Phe-Ser-Lys-Ala- (SEQ ID NO: 3)

IV Ser-Lys-Ala-Phe-Ser-Lys-Ala- Phe-Ser-Lys -Ala-Phe-Ser-Lys-Ala- Phe-Ser-Lys-Ala-Phe- (SEQ ID NO: 4)

V Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser- Lys-Ala-Phe-Ser (SEQ ID NO: 5)

The peptide may have amino acids extending from either end of the chain. For example, the chains may have a Ser-Lys sequence before the "Ala" end, and/or an Ala-Phe sequence after the "Lys" end. Other amino acid sequences may also be attached to the "Ala" and/or the "Lys" end.

Similarly, in any polypeptide chain having at least four groups of amino acids of the sequence as described above, the chain may have, for example, a C-D sequence before the first A-B-C-D group. Also other amino acid sequences may be attached to the "A" and/or the "D" end of one of these polypeptide chains. Also there may be amino acids in the chain which space one or more groups of the hereinabove noted four amino acids from each other. In accordance with another embodiment, the peptide may be a magainin peptide.

A magainin peptide is either a magainin such as magainin I, II or III or an analogue or derivative thereof. The magainin peptides preferably include the following basic peptide structure X₁₂:

- R₁₁-R₁₁-R₁₂-R₁₃-R₁₁-R₁₄-R₁₂-R₁₁- R₁₄-R₁₂-R₁₁-R₁₁-R₁₁-R_14a-(R₁₅)_n-R_14a-R₁₄ -- wherein R₁₁ is a hydrophobic amino acid, R₁₂ is a basic hydrophilic amino acid; R₁₃ is a hydrophobic, neutral hydrophilic, or basic hydrophilic amino acid; R₁₄ and R_14a are hydrophobic or basic hydrophilic amino acids; R₁₅ is glutamic acid or aspartic acid, or a hydrophobic or a basic hydrophilic amino acid, and n is 0 or 1. In a preferred embodiment, R₁₃ is a hydrophobic or neutral hydrophilic amino acid, R_14a is a hydrophobic amino acid, and R₁₄ is glutamic acid or aspartic acid.

Thus, for example, a magainin peptide may include the following structure: -Y₁₂-X₁₂- where X₁₂ is the hereinabove described basic peptide structure and Y₁₂ is

(i)

R₁₂

(ii) R_14a-R₁₂

(iii) R₁₁-R_14a-R₁₂

(iv) R₁₄-R_{1 1} -R_14a-R₁₂ where R₁₁, R₁₂, R₁₄, and R_14a are as previously defined.

A magainin peptide may also have the following structure: -X₁₂-Z₁₂- wherein X is as previously defined and Z₁₂ is:

(i) R₁₆ where R₁₆ is a basic hydrophilic amino acid or asparagine or glutamine.

(ii) R₁₆-R₁₇ where R₁₇ is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid. Preferably, R₁₇ is a neutral hydrophilic amino acid.

A magainin peptide may also have the following structure:

(Y₁₂)_a-X₁₂-(Z₁₂)_b where X₁₂, Y₁₂ and Z₁₂ are as previously defined and a is 0 or 1 and b is 0 or 1.

The magainin peptides may also include the following basic peptide structure X₁₃: R₁₄-R₁₁-R_14a-R₁₂-R₁₁-R₁₁-R₁₂-R₁₃- R₁₁-R₁₄-R₁₂-R₁₁-R₁₁-R₁₂-, whereln R₁₁,R₁₂,R₁₃, R₁₄, andR_14a are amino acids as hereinabove described.

The magainin peptide may also include the following structure X₁₃-Z₁₃; wherein X₁₃ is the hereinabove described basic peptide structure and Z₁₃ is (R₁₁)_n- (R₁₁)_n- (R₁₁)_n- (R_14a)_n- (R₁₅ )_n- (R_14a)_n- (R₁₄)_n-

(R₁₆)_n-(R₁₇)_n Wherein R₁₁, R₁₄, R_14a, R₁₅, R₁₆, and R₁₇ are as hereinabove described, and n is 0 or 1, and each n may be the same or different.

The magainin peptides generally include at least fourteen amino acids and may include up to forty amino acids. A magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove described basic peptide structures of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.

As representative examples of such magainin peptides, there may be mentioned peptides having the following primary sequences as given in the accompanying sequence listing as well as appropriate analogues and derivatives thereof:

(a) (SEQ ID NO:6) (OH) or (NH₂)

(Magainin I)

(b) (SEQ ID NO: 7) (OH) or (NH₂)

(Magainin II)

(c) (SEQ ID NO:8) (OH) or (NH₂)

(Magainin III)

The following are examples of peptide derivatives or analogs of the basic structure:

(d) (SEQ ID NO:9) (OH) or (NH₂)

(e) (SEQ ID NO: 10) (OH) or (NH₂)

(f) (SEQ ID NO: 11) (OH) or (NH₂) Magainin peptides are described in Proc. Natl. Acad Sci. Vol. 84 pp. 5449-53 (Aug. 87). The term "magainin peptides" as used herein refers to the basic magainin structure as well as derivatives and analogs thereof, including but not limited to the representative derivatives or analogs.

In accordance with a further embodiment, the peptide may be a PGLa peptide or an XPF peptide.

A PGLa peptide is either PGLa or an analogue or derivative thereof. The PGLa peptides preferably include the following basic peptide structure X₁₄ :

- R₁₁-R₁₇-R₁₂-R₁₁-R₁₄-R₁₄-R₁₁- R₁₁-R₁₄-R₁₂-R₁₁-R₁₁-R₁₂-R₁₁- R₁₁-R₁₁-R₁₂- where R₁₁, R₁₂, R₁₄, and R₁₇ are as previously defined.

The PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids. Accordingly, the hereinabove described basic peptide structure for a PGLa peptide may include additional amino acids at the amino end or at the carboxyl end or at both the amino and carboxyl end.

Thus, for example, a PGLa peptide may have the following structure: -Y₁₄-X₁₄- where X₁₄ is as previously defined and

Y₁₄ is (i) R₁₁;

( ii) R₁₄-R₁₁ where R₁₁ and R₁₄ are as previously defined.

For example, a PGLa peptide may also have the following structure: -X₁₄-Z₁₄- where X. , is as previously defined; and Z_{1 4} is :

( i) R₁₁; or

( ii) R₁₁-R₁₁ where R₁₁ is as previously defined.

A PGLa peptide may also have the following structure:

(Y₁₄)_a-X₁₄-(Z₁₄)_b where X₁₄; Y₁₄ and Z₁₄ are as previously defined, a is 0 or 1 and b is 0 or 1.

An XPF peptide is either XPF or an analogue or derivative thereof. The XPF peptides preferably include the following basic peptide structure X₁₆:

-R₁₁-R₁₇-R₁₂-R₁₁-R₁₄-R₁₈-R₁₇- R₁₁-R₁₄- R₁₂-R₁₁-R₁₁-R₁₂- R₁₁-R₁₁- R₁₁-R₁₂-(R₁₅ )_n-R₁₁-- , wherein R₁₁, R₁₂, R₁₄, R₁₅ and R₁₇ are as previously defined and R₁₈ is glutamine or asparagine or a basic hydrophilic, or hydrophobic amino acid and, n is 0 or 1.

The XPF peptides generally include at least nineteen amino acids and may include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of XPF may include additional amino acids at the amino end, or at the carboxyl end or at both the amino and carboxyl ends.

Thus, for example, an XPF peptide may include the following structure: -Y₁₆-X₁₆- where X₁₆ is as previously defined and X₁₆ is

(i) R₁₁ or

(ϋ) R₁₄-R₁₁

where R₁₁ and R₁₄ are as previously defined.

An XPF peptide may include the following structure:

-X₁₆-Z₁₆- where X₁₆ is as previously defined and Z₁₆ is

(i) R₁₁; or

(ii) R₁₁-R₁₈; ^or

(iii) R₁₁-R₁₈-Proline; or

(iv) R₁₁-R₁₈-Proline-R₁₂

An XPF peptide may also have the following structure: (Y₁₆)_a-X₁₆-(Z₁₆)_b where X₁₆, Y₁₆ and Z₁₆ are as previously defined: a is 0 or 1 and b is 0 or 1.

Preferred are XPF or PGLa peptides, which are characterized by the following primary amino acid sequences as given in the accompanying sequence listing: PGLa : (SEQ ID NO: 12) (NH₂)

XPF : (SEQ ID NO: 13)

A review of XPF and PGLa can be found in Hoffman et al, EMBO J. 2:711-714, 1983; Andreu, et al, J. Biochem. 149:531-535, 1985; Gibson, et al J. Biol. Chem. 261:5341-5349, 1986; and Giovannini, et al, Biochem J. 243:113-120, 1987.

In accordance with yet another embodiment, the peptide may be a CPF peptide or appropriate analogue or derivative thereof.

CPF peptides as well as analogues and derivatives thereof are herein sometimes referred to collectively as CPF peptides.

The CPF peptide may be one which includes the following basic peptide structure X₂₀: -R₂₁-R₂₁-R₂₂-R₂₂-R₂₁-R₂₁-R₂₃-R₂₁- -R₂₁-R₂₁-R₂₃-R₂₁-R₂₁-R₂₄-R₂₅-R₂₁- wherein R₂₁ is a hydrophobic amino acid;

R₂₂ is a hydrophobic amino acid or a basic hydrophilic amino acid;

R₂₃ is a basic hydrophilic amino acid;

R₂₄ is a hydrophobic or neutral hydrophilic amino acid; and

R₂₅ is a basic or neutral hydrophilic amino acid.

The hereinabove basic structure is hereinafter symbolically indicated as X₂₀. The hydrophobic amino acids are Ala, Cys, Phe, Gly, lle, Leu, Met, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).

The neutral hydrophilic amino acids are Asn, Gln, Ser, Thr, and homoserine (Hse).

The basic hydrophilic amino acids are Lys, Arg, His, Orn, homoarginine (Har), 2,4-diarainobutyric acid (Dbu), and p-aminophenylalanine.

The CPF peptide may include only the hereinabove noted amino acids or may include additional amino acids at the amino and/or carboxyl end or both the amino and carboxyl end. In general, the peptide does not include more than 40 amino acids.

The CPF peptides including the above basic structure preferably have from 1 to 4 additional amino acids at the amino end.

Accordingly, such preferred peptides may be represented by the structural formula:

Y₂₀ - X₂₀ - wherein X₂₀ is the hereinabove described basic peptide structure and Y is

(i) R₂₅-, or

(ii) R₂₂-R₂₅-; or

(iii) R₂₁-R₂₂-R₂₅; or

(iv) R₂₂-R₂₁-R₂₂-R₂₅; preferably

Glycine - R₂₁-R₂₂-R₂₅- wherein R₂₁, R₂₂ and R₂₅ are as previously defined. The carboxyl end of the basic peptide structure may also have additional amino acids which may range from 1 to 13 additional amino acids.

In a preferred embodiment, the basic structure may have from 1 to 7 additional amino acids at the carboxyl end, which may be represented as follows:

-X₂₀ - Z₂₀ wherein

X is the hereinabove defined basic peptide structure and Z₂₀ is

(i) R₂₁-, or

(ii) R₂₁-R₂₁-; or

(iii) R₂₁-R₂₁-R₂₄; or

( iv) R₂₁-R₂₁-R₂₄-R₂₄; or

(v) R₂₁-R₂₁-R₂₄-R₂₄-R₂₆; or

(vi) R₂₁-R₂₁-R₂₄-R₂₄-R₂₆-Gln; or

(vii) R₂₁-R₂₁-R₂₄-R₂₄-R₂₆-Gln-Gln, wherein R₂₁ and R₂₄ are as previously defined, and R₂₆ is proline or a hydrophobic amino acid.

Preferred peptides may be represented by the following structural formula

(Y₂₀)_a - X₂₀ - (Z₂₀)_b wherein X₂₀, Y₂₀ and Z₂₀ are as previously defined and a is 0 or 1 and b is 0 or 1.

Representative examples of CPF peptides which may be employed, some of which have been described in the literature, include the following sequences as given in the accompanying sequence listing:

(SEQ ID NO: 14)

(SEQ ID NO: 15)

(SEQ ID NO: 16)

(SEQ ID NO: 17)

(SEQ ID NO: 18)

(SEQ ID NO: 19)

(SEQ ID NO:20)

(SEQ ID N0:21)

(SEQ ID N0:22)

(SEQ ID N0:23)

(SEQ ID NO: 24)

(SEQ ID NO:25)

(SEQ ID NO: 26)

A review of the CPF peptides can be found in Richter, K.,

Egger, R., and Kreil (1986) J. Biol. Chem 261, 3676-3680;

Wakabayashi, T., Kato, H., and Tachibaba, S. (1985)

Nucleic Acids Research 13, 1817-1828; Gibson, B.W.,

Poulter, L., Williams, D.H., and Maggio, J.E. (1986) J.

Biol. Chem 261, 5341-5349.

In accordance with yet another embodiment, the peptide may include one of the following basic structures

X₃₁ through X₃₇ wherein:

X₃₁ is -[R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂]-_n;

X₃₂ is -[ R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁] -_n;

X₃₃ is -[R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-R₃₂ ] -_n; X₃₄ is -[ R ₃₃-R₃₁ -R₃₂-R₃₂-R₃₁ -R₃₂-R₃₂] -_n ; X35 is -[R₃₁-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₃]-_n;

and

X₃₆ is -[R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁]-_n; X₃₇ ^is -[R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂]-_n;

wherein R₃₁ is a basic hydrophilic amino acid, R₃₂ is a hydrophobic amino acid, R₃₃ is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.

The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2,4-diaminobutyric acid (Dbu), and p-aminophenylalanine.

The hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, lle, Leu, Met, Pro, Val, Trp and Tyr,norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).

The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, Thr, and hσmoserine (Hse).

In accordance with one embodiment, when the peptide includes the structure X₃₁, the peptide may include the following structure:

Y₃₁-X₃₁, wherein X is as hereinabove described, and Y is:

(i) R₃₂;

(ii) R₃₂-R₃₂;

(iii) R₃₁-R₃₂-R₃₂; (iv) R₃₃-R₃₁-R₃₂-R₃₂ ;

(v) R₃₂-R₃₃-R₃₁-R₃₂ -R₃₂ ; or

(vi) R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂, wherein R₃₁, R₃₂, and R₃₃ are as hereinabo e described

In accordance with another embodiment, when the peptide includes the structure X_31, the peptide may include the following structure:

X₃₁-Z₃₁, wherein X₃₁ is as hereinabove described, and Z₃₁ is:

(i) R₃₁;

(ii) R₃₁-R₃₂;

(iii) R₃₁-R₃₂-R₃₂;

(iv) R₃₁-R₃₂-R₃₂-R₃₃;

(v) R₃₁-R₃₂-R₃₂-R₃₃-R₃₁; or

(vi) R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂.

In accordance with yet another embodiment, the peptide may include the following structure: (Y₃₁)_a- X_{3 1} -(Z₃₁)_b, wherein Y₃₁ and Z₃₁ are as previously defined, a is 0 or 1, and b is 0 or 1.

When the peptide includes the structure X₃₂, the peptide may include the following structure:

Y₃₂ - X₃₂, wherein X₃₂ is as hereinabove described, and Y₃₂ is:

(i) R₃₁;

(ii) R₃₂-R₃₁;

(iii) R₃₂-R₃₂-R₃₁;

(iv)

R₃₁-R₃₂-R₃₂-R₃₁; (v) R₃₃-R₃₁-R₃₂-R₃₂-R₃₁; or

(vi) R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁

In another embodiment, when the peptide includes the structure X₃₂, the peptide may include the following structure:

X₃₂ - Z₃₂ , wherein X₃₂ is as hereinabove described, and Z₃₂ is :

( i ) R₃₂ ;

(ii ) R₃₂-R₃₂ ;

(iii) R₃₂-R₃₂-R₃₃ ;

(iv ) R₃₂-R₃₂-R₃₃-R₃₁;

(v) R₃₂-R₃₂-R₃₃-R₃₁-R₃₂ ; or

( vi) R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂.

In accordance with yet another embodiment, the peptide may include the following structure: (Y₃₂)_a- X_{3 2} -(Z₃₂)_b, wherein Y₃₂ and Z₃₂ are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with another embodiment, when the peptide includes the structure X₃₃, the peptide may include the following structure:

Y₃₃ - X₃₃ wherein X₃₃ is as hereinabove described, and Y₃₃ is:

(i) R₃₂;

(ii) R₃₁-R₃₂;

(iii) R₃₂-R₃₁-R₃₂;

(iv) R₃₂-R₃₂-R₃₁-R₃₂;

(v)

R₃₁-R₃₂-R₃₂-R₃₁-R₃₂; or (vi) R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-R₃₂, wherein R₃₁, R₃₂, and R₃₃ are as hereinabove described.

In accordance with another embodiment, when the peptide includes the structure X₃₃, the peptide may include the following structure:

X₃₃ - Z₃₃ wherein X₃₃ is as hereinabove described, and Z₃₃ is:

(i) R₃₂;

(ii) R₃₂-R₃₃;

(iii) R₃₂-R₃₃-R₃₁;

( iv) R₃₂-R₃₃-R₃₁-R₃₂ ;

(v) R₃₂-R₃₃-R₃₁-R₃₂-R₃₂; or

(vi) R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-

In accordance with yet another embodiment, the peptide may include the following structure: (Y₃₃)_a- X_{3 3} -(Z₃₃)_b, wherein Y₃₃ and Z₃₃ are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with yet another embodiment, when the peptide includes the structure X₃₄ , the peptide may include the following structure:

Y₃₄ - X₃₄, wherein X₃₄ is as hereinabove described, and Y₃₄ is:

(i) R₃₂;

(ii) R₃₂-R₃₂;

(iii) R₃₁-R₃₂-R₃₂;

( iv) R₃₂-R₃₁-R₃₂-R₃₂ ; (v) R₃₂-R₃₂-R₃₁-R₃₂-R₃₂; or

(vi) R₃₁-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂, wherein R₃₁, R₃₂ and R₃₃ are as hereinabove described.

In accordance with another embodiment, when the peptide includes the structure X₃₄, the peptide may include the following structure:

X₃₄-Z₃₄, wherein X₃₄ is as hereinabove described, and Z₃₄ is:

34

(i) R₃₃;

(ii) R₃₃-R₃₁;

(iii) R₃₃-R₃₁-R₃₂;

(iv) R₃₃-R₃₁-R₃₂-R₃₂;

(v) R₃₃-R₃₁-R₃₂-R₃₂-R₃₁; or

(vi) R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-R₃₂.

In accordance with yet another embodiment, the peptide may include the following structure: (Y₃₄)_a- X_{3 4} -(Z₃₄)_b, wherein X₃₄ are Z₃₄ are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with a further embodiment, when the peptide includes the structure X₃₅, the peptide may include the following structure:

Y₃₅-X₃₅, wherein X₃₅ is as hereinabove described, and Y₃₅ is:

(i) R₃₃;

(ii) R₃₂-R₃₃;

(iii) R₃₂-R₃₂-R₃₃;

( iv) R₃₁-R₃₂-R₃₂-R₃₃ ; (v) R₃₂-R₃₁-R₃₂-R₃₂-R₃₃; or

(vi) R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₃, wherein R₃₁, R₃₂, and R₃₃ are as hereinabove described.

In accordance with another embodiment, when the peptide includes the structure X₃₅, the peptide may include the following structure:

X₃₅ - Z₃₅ wherein X₃₅ is as hereinabove described, and Z₃₅ is:

(i) R₃₁;

(ii) R₃₁-R₃₂;

(iii) R₃₁-R₃₂-R₃₂;

(iv) R₃₁-R₃₂-R₃₂-R₃₁;

(v) R₃₁-R₃₂-R₃₂-R₃₁-R₃₂; or

(vi) R₃₁-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂.

In accordance with yet another embodiment, the peptide may include the following structure: (Y₃₅)_a- X₃₅ (Z₃₅)_b, wherein X₃₅ and Z₃₅ are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with a further embodiment, when the peptide includes the structure X₃₆, the peptide may include the following structure:

Y₃₆ - X₃₆ wherein X₃₆ is as hereinabove described, and Y_3g is:

(i) R₃₁;

(il) R₃₃-R₃₁;

(iii) R₃₂-R₃₃-R₃₁;

(iv)

R₃₂-R₃₂-R₃₃-R₃₁; (v) R₃₁-R₃₂-R₃₂-R₃₃-R₃₁; or

(vi) R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁, wherein R₃₁, R₃₂, and R₃₃ are as hereinabove described.

In accordance with another embodiment, when the peptide includes the structure X₃₆, the peptide may include the following structure:

X₃₆-Z₃₆, wherein X₃₆ is as hereinabove described, and Z₃₆ is:

(i) R₃₂;

(ii) R₃₂-R₃₂;

(iii) R₃₂-R₃₂-R₃₁;

(iv) R₃₂-R₃₂-R₃₁-R₃₂;

(v) R₃₂-R₃₂-R₃₁-R₃₂-R₃₂; or

(vi) R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₃.

In accordance with yet another embodiment, the peptide may include the following structure:

(Y₃₆)_a- X₃₆ (Z₃₆)_b, wherein Y₃₆ and Z₃₆ are as previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with one embodiment, when the peptide includes the structure X₃₇, the peptide may includes the structure Y₃₇-X₃₇, wherein X₃₇ is as hereinabove described, and Y₃₇ is:

(i) R₃₂;

(ii) R₃₁-R₃₂;

(iii) R₃₃-R₃₁-R₃₂;

(iv) R₃₂-R₃₃-R₃₁-R₃₂;

(v) or

R₃₂-R₃₂-R₃₃- R₃₁-R₃₂; (vi) R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂, wherein R₃₁, R₃₂, andR₃₃ are as hereinabove described.

In accordance with a further embodiment, when the peptide includes the structure X₃₇, the peptide may include the following structure:

X₃₇ - Z₃₇ wherein X₃₇ is as hereinabove described, and Z₃₇ is:

(i) R₃₂;

(ii) R₃₂-R₃₁;

(iii) R₃₂-R₃₁-R₃₂;

(iv) R₃₂-R₃₁-R₃₂-R₃₂;

(v) R₃₂-R₃₁-R₃₂-R₃₂-R₃₃; or

(vi) R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁.

In accordance with yet another embodiment, the peptide may include the following structure:

(Y₃₇) - X₃₇ (Z₃₇)_b, wherein Y₃₇ and Z₃₇ are as previously defined, a is 0 or 1, and b is 0 or 1.

In a preferred embodiment, n is 3, and most preferably the peptide is of one of the following structures as given in the accompanying sequence listing:

(Lys Ile Ala Gly Lys Ile Ala)₃ (SEQ ID NO: 27).

(Lys Ile Ala Lys I le Ala Gly)₃ (SEQ ID NO: 28).

(Lys Ile Ala Gly Lys Ile Gly)₃ (SEQ ID NO: 29).

(Lys Leu Ala Gly Lys Leu Ala)₃ (SEQ ID NO: 30).

(Lys Phe Ala Gly Lys Phe Ala)₃ (SEQ ID NO: 31).

(Lys Ala Leu Ser Lys Ala Leu)₃ (SEQ ID NO: 32).

(Lys Leu Leu Lys Ala Leu Gly)₃ (SEQ ID NO:33). (Lys Ala Ile Gly Lys Ala Ile)₃ (SEQ ID NO: 34).

(Gly Ile Ala Lys Ile Ala Lys)₃ (SEQ ID NO: 35).

(Lys Ile Ala Lys Ile Phe Gly), (SEQ ID NO: 36).

(Gly Ile Ala Arg Ile Ala Lys)₃ (SEQ ID NO:37).

(Lys Phe Ala Arg Ile Ala Giy)₃ (SEQ ID NO: 38).

(Gly Phe Ala Lys Ile Ala Lys)₃ (SEQ ID NO: 39).

(Lys Ile Ala Gly Orn Ile Ala)₃ (SEQ ID NO: 40).

(Lys Ile Ala Arg Ile Ala Gly)₃ (SEQ ID N0:41).

(Orn Ile Ala Gly Lys Ile Ala)₃ (SEQ ID NO:42).

(Gly Ile Ala Arg Ile Phe Lys)₃ (SEQ ID NO:43).

(Lys Nle Ala Gly Lys Nle Ala)₃ (SEQ ID NO: 44).

(Lys Nle Ala Gly Lys Ile Ala)₃ (SEQ ID NO:45).

(Lys Ile Ala Gly Lys Nle Ala)₃ (SEQ ID NO: 46).

(Lys Nva Ala Gly Lys Nva Ala)₃ (SEQ ID NO:47).

(Lys Nva Ala Gly Lys Ile Ala)₃ (SEQ ID NO:48).

(Lys Leu Leu Ser Lys Leu Giy)₃ (SEQ ID NO:49).

(Lys Leu Leu Ser Lys Phe Giy)₃ (SEQ ID NO: 50).

(Lys Ile Ala Gly Lys Nva Ala)₃ (SEQ ID NO:51).

(His Ile Ala Gly His Ile Ala)₃ (SEQ ID NO:52).

(Ala Gly Lys Ile Ala Lys Ile)₃ (SEQ ID NO:53).

(Ile Ala Lys Ile Ala Gly Lys)₃ (SEQ ID NO: 54).

(Lys Ile Ala Gly Arg Ile Ala)₃ (SEQ ID NO:55).

(Arg Ile Ala Gly Arg Ile Ala)₃ (SEQ ID NO: 56).

(Lys Val Ala Gly Lys Ile Ala)₃ (SEQ ID NO:57).

(Lys Ile Ala Gly Lys Val Ala)₃ (SEQ ID NO: 58).

(Ala Lys Ile Ala Gly Lys Ile)₃ (SEQ ID NO:59).

(Orn Ile Ala Gly Orn Ile Ala)₃ (SEQ ID NO: 60). (Lys Phe Ala Gly LysIle Ala)₃ (SEQ ID NO: 61).

(Lys I le Ala Gly Lys Phe Ala)₃ (SEQ ID NO: 62).

(Lys Cha Ala Gly Lys Ile Ala)₃ (SEQ ID NO: 63).

(Lys Nle Ala LysIle Ala Gly)₃ (SEQ ID NO:64).

(Arg I le Ala Gly Lys I le Ala)₃ (SEQ ID NO:65).

(Har I le Ala Gly Har I le Ala)₃ (SEQ ID NO:66).

(Xaa I le Ala Gly Lys I le Ala)₃ (SEQ ID NO: 67).

(Lys I le Ala Gly Xaa Ile Ala)₃ (SEQ ID NO:68).

LysIle Ala (LysIle Ala Gly LysIle Ala) (SEQ ID NO: 69) In (SEQ ID NO:67) and (SEQ ID NO:68), Xaa is p-aminophenylalanine.

In accordance with another embodiment, the amphiphilic peptide includes the following basic structure X₄₀:

R₃₁-R₃₂-R₃₂-R₃₃-R₃₄-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₂-R₃4-R₃₂-R₃₂, wherein R₃₁, R₃₂, and R₃₃ are as hereinabove described, and R_₄ is a basic hydrophilic or hydrophobic amino acid.

In accordance with one embodiment, the peptide may include the following structure:

Y₄₀-X₄₀, wherein X₄₀ is as hereinabove described, and Y₄₀ is:

(i) R₃₂;

(il) R₃₂-R₃₂;

(iii) R_3A-R₃₂-R₃₂;

(iv)

R₃₃-R₃₄-R₃₂-R₃₂; (v) R₃₂-R₃₃-R₃₄-R₃₂-R₃₂ ;

(v) R₃₂-R₃₂-R₃₃-R₃₄-R₃₂-R₃₂. or

(vii) R₃₁-R₃₂-R₃₂-R₃₃-R₃₄-R₃₂-R₃₂, wherein R₃₁, R₃₂, R₃₃ and R₃₃ are as hereinabove described.

In accordance with another embodiment, the peptide may include the following structure:

Y₄₀-X₄₀, wherein X₄₀ is as hereinabove described and

Z₄₀ is:

(i) R₃₁;

(ii) R₃₁-R₃₂;

(iii) R₃₁-R₃₂-R₃₂;

(iv) R₃₁-R₃₂-R₃₂-R₃₃;

(v) R₃₁-R₃₂-R₃₂-R₃₃-R₃₄;

(vi) R₃₁-R₃₂-R₃₂-R₃₃-R₃₄-R₃₂; or

(vii) R₃₁-R₃₂-R₃₂-R₃₃-R₃₄-R₃₂-R₃₂. wherein R₃₁, R₃₂, R₃₃, and R₃₄ are as hereinabove described.

In accordance with yet another embodiment the peptide may include the following structure: ( Y₄₀)_a-X₄₀-(Z₄₀)_b, Wherein Y₄₀ and Z₄₀ are as previously defined, a is 0 or 1, and b is 0 or 1. In a preferred embodiment, the peptide has the following structural formula as given in the accompanying sequence listing:

(SEQ ID NO: 70)

In another preferred embodiment, the peptide has the following structural formula as given in the accompanying sequence listing: (SEQ ID NO: 71)

In accordance with a further embodiment, the peptide has one of the one of the following structural formulae as given in the accompanying sequence listing:

(SEQ ID NO: 72)

(SEQ ID NO: 73)

(SEQ ID NO: 74)

(SEQ ID NO: 75)

(SEQ ID NO: 76)

(SEQ ID NO: 77)

(SEQ ID NO: 78)

(SEQ ID NO: 79)

(SEQ ID NO: 80)

(SEQ ID NO: 81)

(SEQ ID NO: 82)

(SEQ ID NO: 83)

(SEQ ID NO: 84)

(SEQ ID NO: 85)

(SEQ ID NO: 86)

(SEQ ID NO: 87)

In accordance with another embodiment, the peptide may include the following structural formula:

- (LysIle Ala Lys LysIle Ala)-_n, wherein n is from 2 to 5. Preferably, n is 3, and the peptide has the following structural formula:

(LysIle Ala Lys LysIle Ala),

(SEQ ID NO: 88) In accordance with another embodiment, the peptide may include the following structural formula:

-(Lys Phe Ala Lys Lys Phe Ala)- wherein n is from 2 to 5.

Preferably, n is 3, and the peptide has the following structural formula:

(Lys Phe Ala Lys Lys Phe Ala)

(SEQ ID NO: 89)

In accordance with another embodiment, the peptide may include the following structural formula:

-(Lys Phe Ala Lys Lys Ile Ala)- wherein n is from 2 to 5. Preferably n is 3, and the peptide has the following structural formula:

(Lys Phe Ala Lys Lys Ile Ala).

(SEQ ID NO: 90).

In accordance with another embodiment, the peptide may be selected from the group consisting of the following structural formulae as given in the accompanying sequence listing:

(SEQ ID NO: 91)

(SEQ ID NO: 92)

(SEQ ID NO: 93)

(SEQ ID NO: 94)

In accordance with yet another embodiment, the peptide may be a cecropin or sarcotoxin.

The term cecropins includes the basic structure as well as analogues and derivatives thereof. The cecropins and analogues and derivatives thereof are described in Ann. Rev. Microbiol. 1987, Vol. 41, pages 103-26, in particular page 108, and in Christensen, et al., PNAS Vol. 85, pgs. 5072-76, which are hereby incorporated by reference.

The term sarcotoxins includes the basic materials as well as analogues and derivatives thereof. The sarcotoxins and analogues and derivatives thereof are described in Molecular Entomology, pages 369-78, in particular page 375, Alan R. Liss, Inc. (1987), which is hereby incorporated by reference.

In another embodiment, the amphiphilic peptide includes the following basic structure X₅₀: R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁.

R₄₁ is a hydrophobic amino acid, and R₄ is a basic hydrophilic or neutral hydrophilic amino acid.

In one embodiment, the peptide includes the basic structure Y₅₀-X₅₀ wherein X₅₀ is as hereinabove described and Y₅₀ is:

(i) R₄₁;

(ii) R₄₂-R₄₁; or

(iii) R₄₂-R₄₂-R₄₁, wherein R₄₁ and R₄₂ are as hereinabove described.

In one embodiment, R₄₁ is leucine. In another embodiment, R₄₂ is lysine. Representative examples of peptides in accordance with this aspect of the present invention include those having the following structures: (SEQ ID NO: 95 )

(SEQ ID NO: 96)

(SEQ ID NO: 97)

(SEQ ID NO: 98)

In accordance with another embodiment , the amphiphilic peptide includes the following basic structure X

R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁ R₄₂-R₄₂-R₄₁-R₄₂-R₄₂, wherein R₄₁ is a hydrophobic amino acid and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid.

In one embodiment R₄₂ is leucine. In another embodiment, R₄₂ is lysine.

In one embodiment, the peptide includes the basic structure Y₅₂ -X₅₂, wherein X₅₂ is as hereinabove described, and Y₅₂ is:

( i) R₄₂;

( ii) R₄₁-R₄₂;

( iii) R₄₁-R₄₁-R₄₂;

( iv) R₄₂-R₄₁-R₄₁-R₄₂; or

(v)

R₄₂-R₄₂-R₄₁-R₄₁-R₄₂

In one embodiment, the peptide may have the following structure;

Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu

5 10

Leu Lys Lys Leu Arg Arg

15

(SEQ ID NO: 99)

In another embodiment, the peptide includes the basic structure X₅₂ - Z₅₂, wherein X₅₂ is as hereinabove described, and Z₅₂ is:

(i) R₄₁;

(ii) R₄₁-R₄₁;

(iii) R₄₁-R₄₁-R₄₂; (iv) R₄₁-R₄₁-R₄₂-R₄₂; or

(v) R₄₁-R₄₁-R₄₂-R₄₂-R₄₁;

In one embodiment, the peptide may have the following structure:

Lys Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu 5 10

15

(SEQ ID NO: 100)

In another embodiment, the peptide may include the structure:

(Y₅₂)_a - X₅₂ - (Z₅₂)_b, wherein X₅₂, Y₅₂ and Z₅₂ are as hereinabove described, and a is 0 or 1, and b is 0 or 1. In accordance with another embodiment , the peptide includes the following basic structure X_{5 4} : -R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R-

₄₃- ,

wherein R₄₁ and R₄₂ are as hereinabove described, and R₄₃ is a netural hydrophilic amino acid.

In one embodiment, the peptide may have the following structure:

(SEQ ID NO: 101)

In another embodiment, the peptide may have the following structure:

(SEQ ID NO: 102)

In accordance with yet another embodiment, the peptide includes the following basic structure X₅₆:

R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₄, wherein R₄₁ and R ₄₂ are as hereinabove described, and R₄₄ is a neutral hydrophilic amino acid or proline.

In one embodiment, the peptide may include the following structure Y₅₆-X₅₆, wherein X₅₆ is the basic peptide structure hereinabove described, and Y₅₆ is:

(i) -R₄₁

(ii) -R₄₁-R₄₁;

(iii) -R₄₂-R₄₁-R₄₁;

(iv) -R₄₁-R₄₂-R₄₁-R₄₁;

(v) -R₄₁-R₄₁-R₄₂-R₄₁-R₄₁;

(vi) -R₄₂-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁; or

(vii) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁, wherein R₄₁ and R₄₂ are as hereinabove described.

In one embodiment, the peptide may include the structure:

X₅₆-Z₅₆ , wherein X ₅₆ is as

^Z56 ^{is :}

( i) -R₄₂;

( ii) -R₄₂-R₄₂;

(iii) -R₄₂-R₄₂-R₄₁;

( iv) -R₄₂-R₄₂-R₄₁-R₄₁;

(v) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₂;

(vi) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂; or

(vii) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁.

In a preferred embodiment, the peptide may have one of the following structures:

(SEQ ID NO: 103); or

(SEQ ID NO: 104).

In another embodiment, the peptide may have the structure (Y₅₆)_a-X₅₆-(Z₅₆)_b, wherein X₅₆, Y₅₆, and Z₅₆ are as hereinabove described, a is 0 or 1, and b is 0 or 1.

In accordance with another embodiment, the peptide includes the following basic structure X₅₈:

R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₃, wherein R₄₁, R₄₂ and R₄₃are as hereinabove described.

In accordance with another embodiment, the peptide may include the structure Y₅₈-X₅₈, wherein X₅₈ is as hereinabove described, and Y₅₈ is:

(i) -R ₄₁; (ii) -R₄₂-R₄₁;

(iii) -R₄₂-R₄₂-R₄₁;

(iv)

-R₄₁-R₄₂-R₄₂-R₄₁;

(v) -R₄₁-R₄₁-R₄₂-R₄₂-R₄₁;

(V1) -R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁; or

(vii) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁, wherein R₄₁ and R₄₂ are as hereinabove described.

In another embodiment, the peptide includes the structure X₅₈-Z₅₈, wherein X₅₈ is as hereinabove described, and Z₅₈ is:

(i) -R₄₁; (ii) -R₄₁-R45^:

(iii) -R₄₁-R₄₅-R_45;

(iv) -R₄₁-R₄₅-R₄₅_R₄₃;

(v) -R₄₁-R₄₅-R₄₅_R₄₃-R₄₁;

(vi) -R₄₁-R₄₅-R₄₅_R₄₃-R₄₁-R₄₃;

(vii) -R₄₁-R₄₅-R₄₅_R₄₃-R₄₁-R₄₃-R₄₃,

(viii) -R₄₁-R₄₅-R₄₅.R₄₃-R₄₁-R₄₃-R₄₃-R₄₅; or

(ix) -R₄₁-R₄₅-R₄₅_R₄₃-R₄₁-R₄₃-R₄₃-R₄₅-R₄₃, wherein R₄₁ and R₄₃ are as hereinabove described, and R₄₅ is proline.

In one embodiment, the peptide has the following structure:

(SEQ ID NO: 105).

In one embodiment, the peptide may have the structure (Y₅₈)_a-X₅₈-(Z₅₈)_b, Wherein X₅₈, Y₅₈, and Z₅₈ are as hereinabove described, a is 0 or 1, and b is 0 or 1. In accordance with another embodiment , the peptide includes the following basic structure X₆₀ ;

R₄₁- R₄₁-R₄₃ -R₄₂-R₄₁-R₄₁-R₄₁-R₄₁-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-- R₄₂-R₄₁-

R₄₁-R₄₂-R₄₂-R₄₂-R41' wherein R₄₁, R₄₂, and R₄₃ are as hereinabove described. In one embodiment, the peptide may have the following structure:

(SEQ ID NO: 106).

In another embodiment, the peptide may include the structure X₆₀-Z₆₀, wherein X₆₀ is as hereinabove described, and Z₆₀ is:

( i) -R₄₂;

( ii)

-R₄₂-R₄₂;

( iii )

-R₄₂-R₄₂-R₄₁;

( iv)

-R₄₂-R₄₂-R₄₁-R₄₁;

(v) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₂;

(vi) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂; or

(vii) -R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁.

In accordance with yet another embodiment, the peptide has a structure selected from the group consisting of:

^{( a)} R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁;

^{( b )} R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁;

^{( c )} R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-^R41 ;

^{( d )} R₄₂-R₄₂-^R41-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-^R41 ; and

^{( e )} R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁, wherein R₄₁ and R₄₂ are as hereinabove described. In one embodiment, the peptide has the structure

(a), and a representative example of such a structure is (SEQ ID NO: 107), which is given in the accompanying sequence listing.

In another embodiment, the peptide has the structure (b), and a representative example of such a structure is (SEQ ID NO: 108), which is given in the accompanying sequence listing.

In another embodiment, the peptide has the structure (c), and a representative example of such a structure is (SEQ ID NO: 109) as given the accompanying sequence listing.

In yet another embodiment, the peptide has the structure (d), and a representative example of such a structure is (SEQ ID NO: 110) as given in the accompanying sequence listing.

In a further embodiment, the peptide has the structure (e), and representative examples of such a structure are (SEQ ID NO: 111) and (SEQ ID NO: 112) as given in the accompanying sequence listing.

In accordance with another embodiment, the peptide has the following structural formula:

(SEQ ID NO: 113).

In accordance with another embodiment, the peptide is melittin.

Melittin is an amphipathic peptide consisting of 26 amino acid residues, and is isolated from honeybee (Apis mellifera) venom. The peptide is known to be cytolytic.

See Habermann, et al., Hoppe-Seyler's Zeitschrift Phvsiol. Chem., Vol. 348, pgs. 37-50 (1987). Melittin has the following structural formula as represented by the three-letter amino acid code:

Gly Ile Gly Ala Val Leu Lys Val Leu

5

Thr Thr Gly Leu Pro Ala Leu Ile Ser

10 15

Trp Ile Lys Arg Lys Arg Gln Gln

20 25

(SEQ ID NO: 114)

In another embodiment, the peptide purified in accordance with the present invention is an apidaecin. The term apidaecin as used herein includes the basic structure as well as analogues and derivaties thereof. Apidaecins are further described in European Patent Application No. 299,828.

In accordance with another embodiment, the peptide may be an amide - or carboxy-terminated peptide represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide:

Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu

1 2 3 4 5 6 7 8 9 10 11

Lys Lys Leu Leu Lys Lys Leu 12 13 14 15 16 17 18

(SEQ ID NO: 115)

or the peptide may be an analogue of such peptide wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from the peptide.

In one embodiment, at least one of amino acid residues 1, 3, 7, 9, 11, 12, 14, 16, or 18 is deleted from the peptide. In other embodiments, amino acid residues 1 through 3, 1 through 4, 1 through 5, 1 through 6, and 1 through 7 are deleted from the peptide.

In preferred embodiments, amino acid residues 1 through 3 or 1 through 4 are deleted from the peptide, and such peptides have the following structural formulae:

(SEQ ID NO: 116)

(SEQ ID NO: 117)

In accordance with another embodiment, the peptide includes the following structural formula X₆₂:

R₄₁-R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-

R₄₁-R₄₂-R₄₂,

wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid. In one embodiment, R₄₁ is leucine, and in another embodiment, R₄₂ is lysine. In a preferred embodiment, the peptide has the following structure:

Leu Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys 5 10

(SEQ ID NO: 118)

In accordance with another embodiment, the peptide includes the following structural formula X₆₄:

R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂

-R₄₁-R₄₁,

wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid. In one embodiment, R₄₁ is leucine, and in another embodiment, R₄₂ is lysine. In a preferred embodiment, the peptide has the following structural formula:

Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Leu

5 10

(SEQ ID NO: 119)

In another embodiment, the peptide includes the following structural formula X₆₆:

R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁, wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid.

In one embodiment, the peptide may include the following structure:

X₆₆-Z₆₆, wherein X₆₆ is as hereinabove described and Z₆₆ is:

(i) R ₄₂; (ii) R₄₂-R₄₁; or

(iii) R₄₂-R₄₁-R₄₁.

In one embodiment, R₄₁ is leucine, and in another embodiment, R₄₂ is lysine. In a preferred embodiment, the peptide has the following structural formula:

Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Leu Lys

5 10

Leu Leu

15

(SEQ ID NO: 120)

In accordance with yet another embodiment, the amphiphilic peptide or protein may be an ion channel-forming peptide or protein.

Ion channel-forming proteins or peptides which may be employed include defensins, also known as human neutrophil antimicrobial peptides (HNP), major basic protein (MBP) of eosinophils, bactericidal permeability-increasing protein (BPI), and a pore-forming cytotoxin called variously perforin, cytolysin, or pore-forming protein. Defensins are described in Selsted, et al., J. Clin. Invest., Vol. 76, pgs. 1436-1439 (1985). MBP proteins are described in Wasmoen, et al., J. Biol. Chem., Vol. 263, pgs 12559-12563. (1988). BPI proteins are described in Ooi, et al, J. Biol. Chem., Vol. 262, pgs. 14891-14894 (1987). Perforin is described in Henkart, et al., J. Exp. Med., 160: 75 (1984), and in Podack, et al., J. Exo. Med., 160:695 ( 1984) . The above articles are hereby incorporated by reference.

The term ion channel-forming proteins includes the basic structures of the ion channel-forming proteins as well as analogues and derivatives.

The peptides may be produced by known techniques and obtained in substantially pure form. For example, the peptides may be synthesized on an automatic peptide synthesizer. Journal of the American Chemical Society, Vol. 85, pgs. 2149-54 (1963). It is also possible to produce such peptides by genetic engineering techniques. The codons encoding the amino acids are known to those skilled in the art, and thus one may construct DNA encoding any of the peptides by accepted techniques, and clone such DNA into an expression vehicle such as, for example, a plasmid, and transfeet such an expression vehicle into a cell which will express the peptide. Thus, it is contemplated within the scope of the present invention that one may treat a dermatological malignancy by administering transfected cells which include an expression vehicle to a host containing DNA encoding ion channel-forming peρtide(s) or protein(s) such as those hereinabove described.

It is also to be understood that the peptides or proteins may be administered in combination with one another. n accor ance w ano er em o men , ne pep e or protein may be administered in combination with an ion having pharmacological properties.

An ion having pharmacological properties is one which when introduced into a target cell, inhibits and/or prevents and/or destroys the growth of the target cell.

Such an ion having pharmacological properties is one which in the absence of an ion channel-forming peptide or protein is unable to cross a natural or synthetic membrane; in particular a cell membrane, in sufficient amounts to affect a cell adversely.

The peptide or protein and ion having pharmacological properties may be administered as a single composition or in separate compositions, and the single or separate compositions may include additional materials, active and/or inactive, in addition to the peptide or protein and ion having pharmacological properties. As representative examples of ions having pharmacological properties which may be employed, there may be mentioned fluoride, peroxide, bicarbonate, silver, zinc, mercury, copper, platinum, antimony, gold, nickel, selenium, and bismuth ions.

The peptide or protein and ion having pharmacological properties, whether administered or prepared in a single composition or in separate compositions, are employed in amounts effective to inhibit and/or prevent and/or destroy the growth of the dermatological malignancy. In effect, the ion potentiates the action of the peptide, i.e., the amount of the ion is effective to reduce the maximum effective concentration of the peptide or protein for inhibiting growth of a dermatological malignancy.

The ion having pharmacological properties, when used systemically (e.g., intravenously, intraperitoneally, intralesionally), is generally employed in an amount of from 1 mg to 10 mg per kg of host weight. Peptide or protein dosages may be within the ranges hereinabove described.

The ion may be administered in the form of a salt such as, for example, sodium fluoride.

The peptides or proteins may be administered in combination with chemotherapeutic agents such as, but not limited to, cyclophosphamide, cisplatin, dσxorubicin, hexamethylamine, and VP-16.

The invention will now be described with respect to the following examples; however, the scope of the present invention is not intended to be limited thereby.

Example 1

Melanoma cell lines WM239-A (metastatic melanoma), WM278 (primary melanoma), WM793 (primary melanoma),

WM1158 (metastatic melanoma) were seeded in 24-well plates at a concentration of 7.5 x 10⁴ cells/ml containing 2% tumor medium. Peptides (SEQ ID NO: 121), (SEQ ID NO: 122), D-(SEQ ID NO: 121), in which each amino acid residue is a D-amino residue or a glycine residue, and a "control" peptide having the structure of Magainin II (SEQ ID NO: 7), in which the Phe and Lys residues are D-amino acid residues, were frozen at -20°C in 100 ml aliquots at a concentration of 25 mg/ml. Each peptide was then dissolved in sterile distilled water at a dilution of 1:1,000 or 1:5,000 to provide peptide concentrations of 25 μg/ml or 5 μg/ml, respectively. The peptides at the 25 μg/ral or 5 μg/ml concentrations were then added to the plates containing the melanoma cells. The amount of

3

H-thymidine incorporation for each well was taken on days 1, 3, and 7. The percentage of growth reduction of each cell line after 7 days by each peptide is given in

Table 1 below.

Example 2

Peptides (SEQ ID NO: 117) and D-(SEQ ID NO: 117), in which each amino acid residue is a D-amino acid residue, are tested for % growth reduction of melanoma cell lines WM852 (grown in 2% tumor media or PF media), WM983A (grown in 2% tumor media or PF media), WM793 (grown in 2% tumor media), and WM1985 (grown in PF media) according to the procedure of Example 1, except that only a concentration of 25 μg/ml was employed for (SEQ ID NO: 117), and concentrations of 1.0, 2.5, 5.0, 10.0, and 25.0 μg/ml were employed for D-(SEQ ID NO: 117). The results are given in Table II below.

Example 3

The following melanoma cell lines are seeded in 200 ul of 2.0% tumor medium at a density of 1.5 x 10⁴ cells per well in a 96-well microtitor plate:

WM1791A

WM35

WM852

WM983A

WM1366

WM8

WM115

WM983B

WM39

WM1158

SKMel 23

WM164

WM902B

WM793; and

WM239A.

The following day, the media are removed, and solutions of peptides D-(SEQ ID NO: 121) and D-(SEQ ID NO: 117) in 2% tumor media are added in triplicate at the following concentrations:

0 (control)

1.0 μg/ml

5.0 μg/ml

25.0 μg/ml On the next day, 1μCi of 3H-thymidine is added to each well. After 18 hours, the medium was discarded, and the cells were detached by addition of 50 ul of trypsin/versene solution. The loose cells were then harvested using a Tomtec cell harvester. The cells were trapped on filters, and the radioactivity quantitated by liquid scintillation counting using a Packard instrument. The radioactive counts for each cell line contacted with the peptides is given in Table III below.

It is to be understood, however, that the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be particularly described and still be within the scope of the accompanying claims.

SEQUENCE LISTING

(1) GENERAL INFORMATION:

(i) APPLICANT: Jacob, Leonard S.

Maloy, W. Lee

(ii) TITLE OF INVENTION: Treatment of Melanoma with

Biologically Active Peptides

(iii) NUMBER OF SEQUENCES: 122

(iv) CORRESPONDENCE ADDRESS:

(A) ADDRESSEE: Carella, Byrne, Bain, Gilfillan,

Cecchi & Stewart

(B) STREET: 6 Becker Farm Road

(C) CITY: Roseland

(D) STATE: New Jersey

(E) COUNTRY: USA

(F) ZIP: 07068

(v) COMPUTER READABLE FORM:

(A) MEDIUM TYPE: 3.5 inch diskette

(B) COMPUTER: IBM PS/2

(C) OPERATING SYSTEM: PC-DOS

(D) SOFTWARE: DW4.V2

(vi) CURRENT APPLICATION DATA:

(A) APPLICATION NUMBER:

(B) FILING DATE:

(C) CLASSIFICATION:

(vii) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: ( B ) FILING DATE :

(viii) ATTORNEY/AGENT INFORMATION:

(A) NAME: Olstein, Elliot M.

(B) REGISTRATION NUMBER: 24,025

(C) REFERENCE/DOCKET NUMBER: 421250-209

(ix) TELECOMMUNICATION INFORMATION:

(A) TELEPHONE: 201-994-1700

(B) TELEFAX: 201-994-1744

(2) INFORMATION FOR SEQ ID NO:1:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 20 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(x) PUBLICATION INFORMATION:

(H) DOCUMENT NUMBER: W0B9/11290

(I) FILING DATE: 19-MAY-1989

(J) PUBLICATION DATE: 30-NOV-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:

Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe

5 10

Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys

15 20

(2) INFORMATION FOR SEQ ID NO: 2:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(x) PUBLICATION INFORMATION:

(H) DOCUMENT NUMBER: W089/11290

(I) FILING DATE: 19-MAY-1989

(J) PUBLICATION DATE: 30-NOV-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 2: Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe

5 10

Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys

15 20

Ala Phe Ser Lys

( 2 ) INFORMATION FOR SEQ ID NO: 3:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 16 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(x) PUBLICATION INFORMATION:

(H) DOCUMENT NUMBER: W089/11290

(I) FILING DATE: 19-MAY-1989

(J) PUBLICATION DATE: 30-NOV-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 3: Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser

5 10

Lys Ala Phe Ser Lys Ala

15 (2) INFORMATION FOR SEQ ID NO: 4:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 20 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(x) PUBLICATION INFORMATION:

(H) DOCUMENT NUMBER: W089/11290

(I) FILING DATE: 19-MAY-1989

(J) PUBLICATION DATE: 30-NOV-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys

5 10

Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe

15 20

(2) INFORMATION FOR SEQ ID NO: 5:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 16 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(x) PUBLICATION INFORMATION:

(H) DOCUMENT NUMBER: W089/11290

(I) FILING DATE: 19-MAY-1989

(J) PUBLICATION DATE: 30-NOV-1989 (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala

5 10

Phe Ser Lys Ala Phe Ser

15

(2) INFORMATION FOR SEQ ID NO: 6:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 23 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: Magainin I peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Zasloff, Michael

(C) JOURNAL: Proc. Nat. Acad. Sci.

(D) VOLUME: 84

(F) PAGES: 5449-5453

(G) DATE: AUG - 1987

(H) DOCUMENT NUMBER: US 48.10777

(I) FILING DATE: 04-MAR-1987

(J) PUBLICATION DATE: 07-MAR-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 6:

Gly lle Gly Lys Phe Leu His Ser Ala Gly

5 10

Lys Phe Gly Lys Ala Phe Val Gly Glu lle

15 20

Met Lys Ser

(2) INFORMATION FOR SEQ ID NO: 7: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 23 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: Magainin II peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Zasloff, Michael

(C) JOURNAL: Proc. Nat. Acad. Sci.

(D) VOLUME: 84

(F) PAGES: 5449-5453

(G) DATE: AUG - 1987

(H) DOCUMENT NUMBER: US 4810777

(I) FILING DATE: 04-MAR-1987

(J) PUBLICATION DATE: 07-MAR-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7: Gly lle Gly Lys Phe Leu His Ser Ala Lys

5 10

Lys Phe Gly Lys Ala Phe Val Gly Glu lle

15 20

Met Asn Ser

(2) INFORMATION FOR SEQ ID NO: 8:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (ix) FEATURE :

(A) NAME/KEY: Magainin III peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Zasloff, Michael

(C) JOURNAL: Proc. Nat. Acad. Sci.

(D) VOLUME: 84

(F) PAGES: 5449-5453

(G) DATE: AUG - 1987

(H) DOCUMENT NUMBER: US 4810777

(I) FILING DATE: 04-MAR-1987

(J) PUBLICATION DATE: 07-MAR-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8: Gly lle Gly Lys Phe Leu His Ser Ala Lys

5 10

Lys Phe Gly Lys Ala Phe Val Gly Glu lle

15 20

Met Asn

(2) INFORMATION FOR SEQ ID NO: 9:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: magainin peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Zasloff, Michael

(C) JOURNAL: Proc. Nat. Acad. Sci.

(D) VOLUME: 84 (F) PAGES: 5449-5453

(G) DATE: AUG - 1987

(H) DOCUMENT NUMBER: US 4810777

(I) FILING DATE: 04-MAR-1987

(J) PUBLICATION DATE: 07-MAR-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: lle Gly Lys Phe Leu His Ser Ala Lys Lys

5 10

Phe Gly Lys Ala Phe Val Gly Glu lle Met

15 20

Asn Ser

(2) INFORMATION FOR SEQ ID NO: 10:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: magainin peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Zasloff, Michael

(C) JOURNAL: Proc. Nat. Acad. Sci.

(D) VOLUME: 84

(F) PAGES: 5449-5453

(G) DATE: AUG - 1987

(H) DOCUMENT NUMBER: US 4810777

(I) FILING DATE: 04-MAR-1987

(J) PUBLICATION DATE: 07-MAR-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10:

Gly Lys Phe Leu His Ser Ala Lys Lys Phe

5 10

Gly Lys Ala Phe Val Gly Glu lle Met Asn

15 20

Ser

(2) INFORMATION FOR SEQ ID NO: 11:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 20 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: magainin peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Zasloff, Michael

(C) JOURNAL: Proc. Nat. Acad. Sci.

(D) VOLUME: 84

(F) PAGES: 5449-5453

(G) DATE: AUG - 1987

(H) DOCUMENT NUMBER: US 4810777

(I) FILING DATE: 04-MAR-1987

(J) PUBLICATION DATE: 07-MAR-1989

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 11: Lys Phe Leu His Ser Ala Lys Lys Phe Gly

5 10

Lys Ala Phe Val Gly Glu lle Met Asn Ser

15 20

(2) INFORMATION FOR SEQ ID NO: 12: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: PGLa peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Hoffman, et al.

(C) JOURNAL: EMBO J.

(D) VOLUME: 2

(F) PAGES: 711-714

(G) DATE: 1983

(A) AUTHOR: Andreu, et al.

(C) JOURNAL: Journal of Biochemistry

(D) VOLUME: 149

(F) PAGES: 531-535

(G) DATE: 1985

(A) AUTHOR: Gibson, et al.

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 5341-5349

(G) DATE: 1986

(A) AUTHOR: Giovannini, et al.

(C) JOURNAL: Biochem J.

(D) VOLUME: 243

(F) PAGES: 113-120

(G) DATE: 1987 ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 12 Gly Met Ala Ser Lys Ala Gly Ala Ile Ala

5 10

Gly Lys Ile Ala Lys Val Ala Leu Lys Ala

15 20

Leu

(2) INFORMATION FOR SEQ ID NO: 13:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 25 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: XPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Hoffman, et al .1

(C) JOURNAL: EMBO J.

(D) VOLUME: 2

(F) PAGES: 711-714

(G) DATE: 1983

(A) AUTHOR: Andreu, et al.

(C) JOURNAL: Journal of Biochemistry

(D) VOLUME: 149

(F) PAGES: 531-535

(G) DATE: 1985

(A) AUTHOR: Gibson, et al.

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 5341-5349

(G) DATE: 1986

(A) AUTHOR: Giovannini, et al. (C) JOURNAL: Biochem J.

(D) VOLUME: 243

(F) PAGES: 113-120

(G) DATE: 1987

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: Gly Trp Ala Ser Lys lle Gly Gln Thr Leu

5 10

Gly Lys lle Ala Lys Val Gly Leu Lys Glu

15 20

Leu lle Gln Pro Lys

25

(2) INFORMATION FOR SEQ ID NO: 14:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S. (C) JOURNAL : Nucleic Acids Research

(D) VOLUME : 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 5341-5349

(G) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407

(I) FILING DATE: 16-OCT-1989

(J) PUBLICATION DATE: 03-MAY-1990

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: Gly Phe Gly Ser Phe Leu Gly Leu Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Ala

15 20

Leu Gly Gly Ala Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 15:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide. (x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K

Egger, R.

Kreil

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME : 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES : 5341-5349

(C) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407

(I) FILING DATE: 16-OCT-1989

(J) PUBLICATION DATE: 03-MAY-1990

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 15 Gly Leu Ala Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Gly Leu Lys lle Gly Ala His Leu

15 20

Leu Gly Gly Ala Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 16: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME: 13

(F) PAGES: 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 5341-5349

(G) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-1990

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu

5 10

Lys Ala Gly Leu Lys lle Gly Thr His Phe

15 20

Leu Gly Gly Ala Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 17:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

( C ) JOURNAL : Nucleic Acids Research

(D) VOLUME: 13

(F) PAGES: 1817-1828 (G) DATE : 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 5341-5349

(G) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407

(I) FILING DATE: 16-OCT-1989

(J) PUBLICATION DATE: 03-MAY-1990

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17: Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu

5 10

Lys Ala Thr Leu Lys lle Gly Thr His Phe

15 20

Leu Gly Gly Ala Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 18:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R. Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T..

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME : 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 5341-5349

(G) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407

(I) FILING DATE: 16-OCT-1989

(J) PUBLICATION DATE: 03-MAY-1990

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Met

15 20

Leu Gly Gly Thr Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 19:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 3676-3680

(G) DATE: 1986

(A) AUTHOR : Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME: 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 5341-5349

(G) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407

(I) FILING DATE: 16-OCT-1989

(J) PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Ala

15 20

Leu Gly Gly Ala Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 20:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME: 13

(F) PAGES: 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W. Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 5341-5349

(G) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407

(I) FILING DATE: 16-OCT-1989

(J) PUBLICATION DATE: 03-MAY-1990

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Ala

15 20

Leu Gly Gly Ser Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 21:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem. (D) VOLUME :: 261

(F) PAGES : 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME : 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 5341-5349

(G) DATE: 1986

(H) DOCUMENT NUMBER: W090/04407

(I) FILING DATE: 16-OCT-1989

(J) PUBLICATION DATE: 03-MAY-1990

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 21 Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Leu

15 20

Leu Gly Gly Thr Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 22:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear (ii ) MOLECULE TYPE : peptide

( ix ) FEATURE :

( A ) NAME/KEY : CPF peptide .

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 3676-3680

(G) DATE: 1986

(A) AUTHOR : Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME : 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR : Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES : 5341-5349

(G) DATE: 1986

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 22

Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Ala

15 20

Leu Gly Gly Ala Pro Gln Gln

25 (2) INFORMATION FOR SEQ ID NO: 23:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR : Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES : 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME: 13

(F) PAGES : 1817-1828

(G) DATE : 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 5341-5349

(G) DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Met

15 20

Leu Gly Gly Ala Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 24:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research

(D) VOLUME: 13

(F) PAGES: 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W. Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 5341-5349

(G) DATE : 1986

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Ala

15 20

Leu Gly Gly Ser Leu Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 25:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(IX) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION:

(A) AUTHOR: Richter, K.

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 3676-3680

(G) DATE: 1986 (A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL: Nucleic Acids Research

(D) VOLUME: 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR: Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME: 261

(F) PAGES: 5341-5349

(G) DATE : 1986

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Gly Leu Lys lle Gly Thr Asn Phe

15 20

Leu Gly Gly Ala Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 26:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide. (x) PUBLICATION INFORMATION:

(A) AUTHOR : Richter, K

Egger, R.

Kreil

(C) JOURNAL: J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 3676-3680

(G) DATE: 1986

(A) AUTHOR: Wakabayashi, T.

Kato, H.

Tachibaba, S.

(C) JOURNAL : Nucleic Acids Research (D) VOLUME : 13

(F) PAGES : 1817-1828

(G) DATE: 1985

(A) AUTHOR : Gibson, B.W.

Poulter, L.

Williams, D.H.

Maggio, J.E.

(C) JOURNAL : J. Biol. Chem.

(D) VOLUME : 261

(F) PAGES : 5341-5349

(G) DATE: 1986

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26: Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys lle Gly Ala Asn Ala

15 20

Leu Gly Gly Ser Pro Gln Gln

25

(2) INFORMATION FOR SEQ ID NO: 27:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 27: Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Lys lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 28:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 28: Lys lle Ala Lys lle Ala Gly Lys lle Ala

5 10

Lys lle Ala Gly Lys lle Ala Lys lie Ala

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 29:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 29: Lys lle Ala Gly Lys lle Gly Lys lle Ala

5 10

Gly Lys lle Gly Lys lle Ala Gly Lys lle

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 30:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30: Lys Leu Ala Gly Lys Leu Ala Lys Leu Ala

5 10

Gly Lys Leu Ala Lys Leu Ala Gly Lys Leu

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 31:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31: Lys Phe Ala Gly Lys Phe Ala Lys Phe Ala

5 10 Gly Lys Phe Ala Lys Phe Ala Gly Lys Phe

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 32:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32: Lys Ala Leu Ser Lys Ala Leu Lys Ala Leu

5 10

Ser Lys Ala Leu Lys Ala Leu Ser Lys Ala

15 20

Leu

(2) INFORMATION FOR SEQ ID NO: 33:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33: Lys Leu Leu Lys Ala Leu Gly Lys Leu Leu

5 10

Lys Ala Leu Gly Lys Leu Leu Lys Ala Leu

15 20

Gly (2) INFORMATION FOR SEQ ID NO: 34:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34: Lys Ala lle Gly Lys Ala lle Lys Ala lle

5 10

Gly Lys Ala lle Lys Ala lle Gly Lys Ala

15 20 lle

(2) INFORMATION FOR SEQ ID NO: 35:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 35: Gly lle Ala Lys lle Ala Lys Gly lle Ala

5 10

Lys lle Ala Lys Gly lle Ala Lys lle Ala

15 20

Lys

(2) INFORMATION FOR SEQ ID NO: 36:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36: Lys lle Ala Lys lle Phe Gly Lys lle Ala

5 10

Lys lle Phe Gly Lys lle Ala Lys lle Phe

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 37:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 37: Gly lle Ala Arg lle Ala Lys Gly lle Ala

5 10

Arg lle Ala Lys Gly lle Ala Arg lle Ala

15 20

Lys

(2) INFORMATION FOR SEQ ID NO: 38:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 ammo acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38:

Lys Phe Ala Arg lle Ala Gly Lys Phe Ala

5 10

Arg lle Ala Gly Lys Phe Ala Arg lle Ala

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 39:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 39:

Gly Phe Ala Lys lle Ala Lys Gly Phe Ala

5 10

Lys lle Ala Lys Gly Phe Ala Lys lle Ala

15 20

Lys

(2) INFORMATION FOR SEQ ID NO: 40:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is ornithine (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40: Lys lle Ala Gly Xaa lle Ala Lys lle Ala

5 10

Gly Xaa lle Ala Lys lle Ala Gly Xaa lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 41:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 41: Lys lle Ala Arg lle Ala Gly Lys lle Ala

5 10

Arg lle Ala Gly Lys lle Ala Arg lle Ala

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 42:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is ornithine (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42:

Xaa lle Ala Gly Lys lle Ala Xaa lle Ala

5 10

Gly Lys lle Ala Xaa lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 43:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 43:

Gly lle Ala Arg lle Phe Lys Gly lle Ala

5 10

Arg lle Phe Lys Gly lle Ala Arg lle Phe

15 20

Lys

(2) INFORMATION FOR SEQ ID NO: 44:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norleucine. (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44:

Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala

5 10

Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 45:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaais norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45:

Lys Xaa Ala Gly Lys lle Ala Lys Xaa Ala

5 10

Gly Lys lle Ala Lys Xaa Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 46:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE: (D) OTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46:

Lys lle Ala Gly Lys Xaa Ala Lys lle Ala

5 10

Gly Lys Xaa Ala Lys lle Ala Gly Lys Xaa

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 47:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 2.1 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 47:

Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala

5 10

Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 48:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (ix) FEATURE :

(D) OTHER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48:

Lys Xaa Ala Gly Lys lle Ala Lys Xaa Ala

5 10

Gly Lys lle Ala Lys Xaa Ala Gly Lys Xaa

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 49:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49:

Lys Leu Leu Ser Lys Leu Gly Lys Leu Leu

5 10

Ser Lys Leu Gly Lys Leu Leu Ser Lys Leu

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 50:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50: Lys Leu Leu Ser Lys Phe Gly Lys Leu Leu

5 10

Ser Lys Phe Gly Lys Leu Leu Ser Lys Phe

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 51:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51:

Lys lle Ala Gly Lys Xaa Ala Lys lle Ala

5 10

Gly Lys Xaa Ala Lys lle Ala Gly Lys Xaa

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 52:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52: His lle Ala Gly His lle Ala His lle Ala

5 10

Gly His lle Ala His lle Ala Gly His lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 53:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 53: Ala Gly Lys lle Ala Lys lle Ala Gly Lys

5 10

lle Ala Lys lle Ala Gly Lys lle Ala Lys

15 20 lle

(2) INFORMATION FOR SEQ ID NO: 54:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54: lle Ala Lys lle Ala Gly Lys lle Ala Lys

5 10

lle Ala Gly Lys lle Ala Lys lle Ala Gly

15 20

Lys

(2) INFORMATION FOR SEQ ID NO: 55:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 55: Lys lle Ala Gly Arg lle Ala Lys lle Ala

5 10

Gly Arg lle Ala Lys lle Ala Gly Arg lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 56:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 56: Arg lle Ala Gly Arg lle Ala Arg lle Ala

5 10 Gly Arg lle Ala Arg lle Ala Gly Arg lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 57-:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE:, peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 57: Lys Val Ala Gly Lys lle Ala Lys Val Ala

5 10

Gly Lys lle Ala Lys Val Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 58:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 58: Lys lle Ala Gly Lys Val Ala Lys lle Ala

5 10

Gly Lys Val Ala Lys lle Ala Gly Lys Val

15 20

Ala (2) INFORMATION FOR SEQ ID NO: 59:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59:

Ala Lys lle Ala Gly Lys lle Ala Lys lle

5 10

Ala Gly Lys lle Ala Lys lle Ala Gly Lys

15 20

lle

(2) INFORMATION FOR SEQ ID NO: 60:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaais ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60: Xaa lle Ala Gly Xaa lle Ala Xaa lle Ala

5 10

Gly Xaa lle Ala Xaa lle Ala Gly Xaa lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 61: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61:

Lys Phe Ala Gly Lys lle Ala Lys Phe Ala

5 10

Gly Lys lle Ala Lys Phe Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 62:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 62: Lys lle Ala Gly Lys Phe Ala Lys lle Ala

5 10

Gly Lys Phe Ala Lys lle Ala Gly Lys Phe

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 63:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS: (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is cyclohexylalanine .

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63:

Lys Xaa Ala Gly Lys lle Ala Lys Xaa Ala

5 10

Gly Lys lle Ala Lys Xaa Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 64:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS :

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaais norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 64:

Lys Xaa Ala Lys lle Ala Gly Lys Xaa Ala

5 10

Lys lle Ala Gly Lys Xaa Ala Lys lle Ala

15 20

Gly

(2) INFORMATION FOR SEQ ID NO: 65:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 AMINO ACIDS (B) TYPE: amino acids

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 65:

Arg lle Ala Gly Lys lle Ala Arg lle Ala

5 10

Gly Lys lle Ala Arg lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 66:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is homoarginine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66:

Xaa lle Ala Gly Xaa lle Ala Xaa lle Ala

5 10

Gly Xaa lle Ala Xaa lle Ala Gly Xaa lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 67:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS :

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE: Xaa is p-aminophenylalanine

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67:

Xaa lle Ala Gly Lys lle Ala Xaa lle Ala

5 10

Gly Lys lle Ala Xaa lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 68:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE: Xaais p-aminophenylalanine

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68: Lys lle Ala Gly Xaa lle Ala Lys lle Ala

5 10

Gly Xaa lle Ala Lys lle Ala Gly Xaa lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 69:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69:

Lys lle Ala Lys lle Ala Gly Lys lle Ala

5 10

Lys lle Ala Gly Lys lle Ala Lys lle Ala

15 20

Gly Lys lle Ala

(2) INFORMATION FOR SEQ ID NO: 70:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 70: Lys Leu Ala Ser Lys Ala Gly Lys lle Ala Gly

5 10

Lys lle Ala Lys Val Ala Leu Lys Ala Leu

15 20

(2) INFORMATION FOR SEQ ID NO: 71:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (ix) FEATURE :

(D) OTHER INFORMATION: Xaa is ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71:

Lys lle Ala Gly Lys lle Ala Lys lle Ala Gly

5 10

Xaa lle Ala Lys lle Ala Gly Lys lle Ala

15 20

(2) INFORMATION FOR SEQ ID NO: 72:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 72:

Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Arg lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 73:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norleucine. (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73:

Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Xaa lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 74:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74:

Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Xaa lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 75:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE: (D) OTHER INFORMATION: Xaa is ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75:

Lys Phe Ala Gly Lys Phe Ala Lys Phe Ala Gly

5 10

Xaa Phe Ala Lys Phe Ala Gly Lys Phe Ala

15 20

(2) INFORMATION FOR SEQ ID NO: 76:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaais ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76:

Lys lle Ala Gly Lys Phe Ala Lys lle Ala

5 10

Gly Xaa Phe Ala Lys lle Ala Gly Lys Phe

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 77:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (ix) FEATURE :

(D) OTHER INFORMATION: Xaa at residues 6, 13, and 20 is norleucine; Xaa at residue 12 is ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77:

Lys lle Ala Gly Lys Xaa Ala Lys lle Ala

5 10

Gly Xaa Xaa Ala Lys lle_. Ala Gly Lys Xaa

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 78:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 78:

Lys Met Ala Ser Lys Ala Gly Lys lle Ala

5 10

Gly Lys lle Ala Lys Val Ala Leu Lys Ala

15 20

Leu

(2) INFORMATION FOR SEQ ID NO: 79:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79

Lys lle Ala Ser Lys Ala Gly Lys lle Ala

5 10

Gly Lys lle Ala Lys Val Ala Leu Lys Ala Leu

15 20

(2) INFORMATION FOR SEQ ID NO: 80:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 80:

Lys lle Ala Ser Lys Ala Gly Lys Xaa Ala

5 10

Gly Lys lle Ala Lys Val Ala Leu Lys Ala Leu

15 20

(2) INFORMATION FOR SEQ ID NO: 81:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norleucine. (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:

Lys Leu Ala Ser Lys Ala Gly Lys Xaa Ala

5 10

Gly Lys lle Ala Lys Val Ala Leu Lys Ala

15 20

Leu

(2) INFORMATION FOR SEQ ID NO: 82:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82:

Lys Xaa Ala Ser Lys Ala Gly Lys Xaa Ala

5 10

Gly Lys lle Ala Lys Val Ala Leu Lys Ala Leu

15 20

(2) INFORMATION FOR SEQ ID NO: 83:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION : Xaa is p- aminophenylalanine (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83:

Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Xaa lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 84:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 84: Lys lle Ala Gly Ala lle Ala Lys lle Ala

5 10

Gly Lys lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 85:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85:

Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Ala lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 86:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86: Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Lys lle Ala Lys lle Ala Gly Ala lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 87:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87: Lys Leu Ala Ser Lys Ala Ala Lys lle Ala

5 10

Ala Lys lle Ala Lys Val Ala Leu Lys Ala 10 20

Leu

(2) INFORMATION FOR SEQ ID NO: 88:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 88:

Lys lle Ala Lys Lys lle Ala Lys lle Ala

5 10

Lys Lys lle Ala Lys lle Ala Lys Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 89:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89: Lys Phe Ala Lys Lys Phe Ala Lys Phe Ala

5 10

Lys Lys Phe Ala Lys Phe Ala Lys Lys Phe

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 90: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 90: Lys Phe Ala Lys Lys lle Ala Lys Phe Ala

5 10

Lys Lys lle Ala Lys Phe Ala Lys Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 91:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 91: Ala lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Lys lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 92:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 92:

Lys lle Ala Gly Lys lle Ala Ala lle Ala

5 10

Gly Lys lle Ala Lys lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 93:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 93: Lys lle Ala Gly Lys lle Ala Lys lle Ala

5 10

Gly Lys lle Ala Ala lle Ala Gly Lys lle

15 20

Ala

(2) INFORMATION FOR SEQ ID NO: 94:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94: Gly Met Ala Ser Lys Ala Gly Lys lle Ala

5 10

Gly Lys lle Ala Lys Val Ala Leu Lys Ala

15 20

Leu

(2) INFORMATION FOR SEQ ID NO: 95:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 11 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 95: Leu Lys Lys Leu Lys Lys Leu Leu Lys Leu

5 10

Leu

(2) INFORMATION FOR SEQ ID NO: 96:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 12 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96: Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys

5 10

Leu Leu

(2) INFORMATION FOR SEQ ID NO: 97: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 13 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 97:

Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu

5 10

Lys Leu Leu

(2) INFORMATION FOR SEQ ID NO: 98:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 98:

Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu

5 10

Leu Lys Leu Leu

(2) INFORMATION FOR SEQ ID NO: 99:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 16 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide

(ix) SEQUENCE DESCRIPTION: SEQ ID NO: 99:

Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Arg Arg

5 10 15

(2) INFORMATION FOR SEQ ID NO: 100:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 16 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100:

Lys Leu Lys Lys Leu Leu Lys Lys Leu Lys

5 10

Lys Leu Leu Lys Leu Leu

15

(2) INFORMATION FOR SEQ ID NO: 101:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101:

Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys

5 10

Leu Leu Lys Lys Asn ..

15 (2) INFORMATION FOR SEQ ID NO: 102:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: Xaa is homoserine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102:

Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys

5 10

Leu Leu Lys Lys Xaa

15

(2) INFORMATION FOR SEQ ID NO: 103:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 18 amino acids

(B) TYPE: ammo acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 103:

Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys

5 10

Asn Lys Lys Leu Leu Lys Lys Leu

15

(2) INFORMATION FOR SEQ ID NO: 104:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 18 ammo acids

(B) TYPE: ammo acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104: Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys

5 10

Pro Lys Lys Leu Leu Lys Lys Leu

15

(2) INFORMATION FOR SEQ ID NO: 105:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105:

Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys

5 10

Lys Leu Gln Gly Pro Pro Gln Gly Gln Ser

15 20

Pro Gln

(2) INFORMATION FOR SEQ ID NO: 106:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 20 ammo acids

(B) TYPE: ammo acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:

Leu Ala Ser Lys Ala Gly Ala lle Ala Gly

5 10

Lys lle Ala Lys Lys Leu Leu Lys Lys Leu

15 20

(2) INFORMATION FOR SEQ ID NO: 107:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 7 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107: Leu Lys Lys Leu Lys Lys Leu

5

(2) INFORMATION FOR SEQ ID NO: 108:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 8 ammo acids

(B) TYPE: ammo acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 108: Leu Leu Lys Lys Leu Lys Lys Leu

5

(2) INFORMATION FOR SEQ ID NO: 109:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 9 ammo acids

(B) TYPE: amino acid

(C) STRANDEDNESS: (D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109: Lys Leu Leu Lys Lys Leu Lys Lys Leu

5

(2) INFORMATION FOR SEQ ID NO: 110:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 10 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110: Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu

5 10

(2) INFORMATION FOR SEQ ID NO: 111:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 11 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111: Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu

5 10

(2) INFORMATION FOR SEQ ID NO: 112:

(i) SEQUENCE CHARACTERISTICS (A) LENGTH: 11 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112: Ala Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu

5 10

(2) INFORMATION FOR SEQ ID NO: 113:

(i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113:

Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu

5 10

Leu Lys Arg

(2) INFORMATION FOR SEQ ID NO: 114:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 26 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(vi) ORIGINAL SOURCE

(A) ORGANISM: Apis mellifera (xii) FEATURE

(A) NAME/KEY: melittin peptide

(x) PUBLICATION INFORMATION:

(A) AUTHORS: Habermann, E.

Jentsch, J.

(B) TITLE: Seguenzanalyse des Melittins aus den tryptischen and peptischen Spaltstucken

(C) JOURNAL: Hoppe-Seyler's Zeitschrift

Physiol. Chem.

(D) VOLUME: 348

(F) PAGES: 37-50

(G) DATE: 1987

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 114:

Gly lle Gly Ala Val Leu Lys Val Leu

5

Thr Thr Gly Leu Pro Ala Leu lle Ser Trp

10 15

lle Lys Arg Lys Arg Gln Gln

20 25

(2) INFORMATION FOR SEQ ID NO: 115:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 18 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 115:

Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys

5 10 Leu Lys Lys Leu Leu Lys Lys Leu

15

(2) INFORMATION FOR SEQ ID NO: 116:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 15 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: C-terminal amide, may be acetylated at N-terminus.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116:

Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys

5 10

Leu Leu Lys Lys Leu

15

(2) INFORMATION FOR SEQ ID NO: 117:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: C-terminal amide, may be acetylated at N-terminus.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 117: Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu

5 10

Leu Lys Lys Leu

(2) INFORMATION FOR SEQ ID NO: 118:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118: Leu Leu Lys Leu Leu Lys Lys Leu Leu Lys

5 10

Lys Leu Lys Lys

(2) INFORMATION FOR SEQ ID NO: 119:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 14 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 119:

Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu

5 10

Lys Lys Leu Leu

(2) INFORMATION FOR SEQ ID NO: 120:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 16 amino acids

(B) TYPE: amino acid (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 120: Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys

5 10

Lys Leu Leu Lys Leu Leu

15

(2) INFORMATION FOR SEQ ID NO: 121:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121: Gly lle Gly Lys Phe Leu Lys Ser Ala Lys

5 10

Lys Phe Gly Lys Ala Phe Val Lys lle Leu

15 20

Asn Ser

(2) INFORMATION FOR SEQ ID NO: 122:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 122: Gly lle Gly Lys Phe Leu Lys Lys Ala Lys

5 10

Lys Phe Ala Lys Ala Phe Val Lys lle lle

15 20 sn Asn

Claims

WHAT IS CLAIMED IS:

1. A process for treating a dermatological malignancy in a host, comprising:

administering to a host at least one biologically active amphiphilic ion channel-forming peptide or protein, said peptide or protein being administered in an amount effective to treat a dermatological malignancy in a host.

2. The process of Claim 1 wherein said peptide or protein is selected from the group consisting of:

(a) magainin peptides;

(b) PGLa peptides;

(c) XPF peptides;

(d) CPF peptides;

(e) cecropins;

(f) sarcotoxins;

(g) a peptide including one of the following basic

structures X₃₁ through X₃₇, wherein:

X₃₁ is -[R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂

X₃₂is -[R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁

X₃₃ i^S -[R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-R₃₂

X₃₄is -[ R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂

X₃₅ is -[R₃₁-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₃

X₃₆ is -[R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁ and

X₃₇is -[R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂

wherein R₃₁ is a basic hydrophilic amino acid, R₃₂ is a hydrophobic amino acid, R₃₃ is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5;

(h) a peptide including the following basic structure X₄₀: R₃₁-R₃₂-R₃₂-R₃₃-R₃₃-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₂-R₃₄-R₃₂-R₃₂, wherein R₃₁ is a basic hydrophilic amino acid, R₃₂ is a

hydrophobic amino acid, R₃₃ is a neutral hydrophilic or

hydrophobic amino acid, and R₃₄ is a basic hydrophilic or

hydrophobic amino acid;

(i) a peptide including the following basic structure X₅₀: R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁-, wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophobic amino acid;

(j) a peptide including the following basic structure X₅₂: R₄₂- R₄₁-R₄₂-R₄₂- R₄₁-R₄₁-R₄₂-R₄₂- R₄₁-R₄₂-R₄₂-, wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid;

(k) a peptide including the following basic structure X ₅₄ - R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁- R₄₁- R₄₂-R₄₂-R₄₃-, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R₄₃ is a neutral hydrophilic amino acid;

(l) a peptide including the following basic structure X₅₆: -R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₄-, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R₄₄ is a neutral hydrophilic amino acid or proline;

(m) a peptide including the following basic structure X₅₈: -R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₃, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic

hydrophilic or neutral hydrophilic amino acid, and R ₄₃ is a neutral hydrophilic amino acid;

(n) a peptide including the following basic structure X ₆₀: - R₄₁-R₄₁-R43-R₄₂-R₄₁-R₄₁-R₄₁-R₄₁-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁- R₄₂-R₄₂-R₄₁- R₄₁-R₄₂-R₄₂-R₄₂-R₄₁, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R₄₃ is a neutral hydrophilic amino acid;

(o) a peptide having a structure selected from the group consisting of:

(i) R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁;

(ii) R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄2-R₄₂-R₄₁;

(iii) R₄₂-R4i-R4i-R₄₂-R₄2-R₄₁-R₄₂-R₄₂-R₄₁;

(iv) R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁; and

(v) R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁, wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic _hydrophilic amino acid or a neutral hydrophilic amino acid; (p) a peptide, said peptide being an amide - or carboxy-terminated peptide represented by the following

structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide:

Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu

1 2 3 4 5 6 7 8 9 10 11

Lys Lys Leu Leu Lys Lys Leu

12 13 14 15 16 17 18

or an analogue of said peptide wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from the peptide;

(q) a peptide including the following structural formula X₆₂:

R₄₁-R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂, wherein R₄₁ is a hydrophobic amino acid, and R₄-is a basic hydrophilic or neutral hydrophilic amino acid;

(r) a peptide including the following structural formula X 6,4"

R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁, wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid;

(s) a peptide including the following structural formula X₆₆:

R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁,

wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid;

(t) melittin;

(u) apidaecins;

(v) defensins;

(w) major basic protein of eosinophils;

(x) bacterial permeability-increasing protein; and

(y) perforin.

3. The process of Claim 2 wherein the peptide is a

magainin peptide.

4. The process of Claim 2 wherein the peptide is a PGLa peptide.

5 . The process of Claim 2 wherein the peptide is an XPF peptide.

6. The process of Claim 2 wherein the peptide is a CPF peptide.

7. The process of Claim 2 wherein the peptide is a cecropin.

8. The process of Claim 2 wherein the peptide is a sarcotoxin.

9. The process of Claim 2 wherein the peptide includes one of the following basic structures X₃₁ through X₃₇, wherein:

X₃₁ is -[R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂

X₃₂ is -[R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁

X₃₃ is -[R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-R₃₂

X₃₄ is -[R₃₃-R₃₁-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂

X₃₅ is -[R₃₁-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃3

X₃₆ is -[R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁ and

X₃₇ is -[R₃₂-R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂ wherein R₃₁ is a basic hydrophilic amino acid, R₃₂ is a hydrophobic amino acid, R₃₃ is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.

10. The process of Claim 2 wherein the peptide includes the following basic structure X₄₀:

R₃₁-R₃₂-R₃₂-R₃₃-R₃4-R₃₂-R₃₂-R₃₁-R₃₂-R₃₂-R₃₂-R₃4-R₃₂-R₃₂,

wherein R₃₁ is a basic hydrophilic amino acid, R₃₂ is a

hydrophobic amino acid, R₃₃ is a neutral hydrophilic or

hydrophobic amino acid, and R₃₄ is a basic hydrophilic or

hydrophobic amino acid.

11. The process of Claim 2 wherein said peptide includes the following basic structure X₅₀:

R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁,

wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid.

12. The process of Claim 2 wherein said peptide includes the following basic structure X₅₂:

R₄₂-R₄₁-R₄₂-R₄₂-R₄₁- R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂, wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid.

13. The process of Claim 2 wherein the peptide includes the following basic structure X₅₄:

-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₃-, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic

hydrophilic or neutral hydrophilic amino acid, and R₄₃ is a neutral hydrophilic amino acid.

14. The process of Claim 2 wherein the peptide includes the following basic structure X₅₆:

-R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₄-, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R₄₄ is a neutral hydrophilic amino acid or proline.

15. The process of Claim 2 wherein the peptide includes the following basic structure X₅₈:

-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₃-, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R₄₃ is a neutral hydrophilic amino acid.

16. The process of Claim 2 wherein the peptide includes the following basic structure X₆₀:

-R₄₁-R₄₁-R₄₃-R₄₂-R₄₁-R₄₁-R₄₁-R₄₁-R₄₁-R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁- -R₄₁-R₄₂-R₄₂-R₄₂-R₄₁-, wherein R₄₁ is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R₄₃ is a neutral hydrophilic amino acid.

17. The process of Claim 2 wherein the peptide has a structure selected from the group consisting of:

(i) R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁;

(ii) R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁;

( iii) R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁;

(iv) R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁; ^and

(v) R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁, wherein R₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic amino acid or a neutral hydrophilic amino acid.

18. The process of Claim 2 wherein said peptide is an amide - or carboxy-terminated peptide represented by the

following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide: Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu

1 2 3 4 5 6 7 8 9 10 11

Lys Lys Leu Leu Lys Lys Leu

12 13 14 15 16 17 18

or an analogue of said peptide wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from the peptide.

19. The process of Claim 2 wherein said peptide includes the following structural formula X₆₂:

R₄₁-R₄₁-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂, wherein R₄₁ is a hydrophobic amino acid, and R₄₇ is a basic hydrophilic or neutral hydrophilic amino acid.

20. The process of Claim 2 wherein said peptide includes the following structural formula X₆₄:

R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁, wherein R₄₁is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid.

21. The process of Claim 2 wherein said peptide includes the following structural formula X₆₆:

R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂-R₄₁-R₄₁,

wherein R₄₁ is a hydrophobic amino acid, and R₄- is a basic hydrophilic or neutral hydrophilic amino acid.

22. The process of Claim 2 wherein said peptide is

melittin.

23. The process of Claim 2 wherein said peptide is an apidaecin.

24. The process of Claim 2 wherein said peptide or protein is a defensin.

25. The process of Claim 2 wherein said peptide or protein is major basic protein of eosinophils.

26. The process of Claim 2 wherein said peptide or protein is bacterial permeability-increasing protein.

27. The process of Claim 2 wherein said peptide or protein is perforin.

28. The process of Claim 2 wherein the peptideis

administered intralesionally.

29. A process for treating a dermatological malignancy in a host, comprising:

administering to a host cells transformed with an expression vehicle including DNA encoding at least one biologically active amphiphilic ion channel-forming peptide or protein, said cells being adminsitered in an amount effective to treat a

dermatological malignancy in a host.

30. The process of Claim 1 wherein said dermatological malignancy is melanoma.