EP0671930A4

EP0671930A4 - Prophylaxis and treatment of adverse oral conditions with biologically active peptides.

Info

Publication number: EP0671930A4
Application number: EP92915677A
Authority: EP
Inventors: Barry Berkowitz; Leonard Jacob
Original assignee: Magainin Pharmaceuticals Inc
Current assignee: Magainin Pharmaceuticals Inc
Priority date: 1991-07-25
Filing date: 1992-07-09
Publication date: 1996-02-07
Also published as: AU2323792A; AU667479B2; CA2074626A1; JPH07502979A; WO1993001723A1; EP0671930A1

Abstract

A process for preventing or treating an adverse oral condition(s) which comprises administering to a host at least one biologically active peptide or protein. The peptide or protein is an ion channel-forming peptide or protein. The peptides or proteins are effective against bacteria, fungi, or viruses associated with plaque, gingivitis, dental caries, periodontal disease, dental implant infections, and other oral or dental conditions.

Description

PROPHYLAXIS AND TREATMENT OF ADVERSE ORAL CONDITIONS WITH BIOLOGICALLY ACTIVE PEPTIDES

This application is a continuation-in-part of application Serial No. 735,070, filed July 25, 1991.

This application relates to the prevention and treatment of adverse oral conditions. More particularly, this application relates to the prevention and treatment of adverse oral conditions such as peridontal disease, gingivitis, plaque, halitosis, and dental caries, by employing a biologically active peptide.

In accordance with an aspect of the present invention, there is provided a process for preventing and/or treating an adverse dental condition(s) comprising administering to a host at least one biologically active amphiphilic peptide or biologically active protein. The peptide or protein is an ion channel-forming peptide or protein. The composition is administered in an amount effective to prevent or treat adverse oral conditions in a host.

The term "adverse oral conditions" as used herein is intended to mean any condition which adversely affects the oral cavity, including but not limited to teeth, gums, tongue, and the oral imicosa. Such adverse dental conditions include, but are not limited to, plaque; peridontitis, including chronic peridontitis, adult

-1- peridontitis, and juvenile peridontitis; gingivitis, including acute necrotizing ulcerative gingivitis, halitosis, and dental caries, including root surface caries and superficial caries.

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. 5072-76 (July, 1988) describes methodology which indicates whether or not a peptide or protein 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 is a peptide which includes both hydrophobic and hydrophilic peptide regions.

The ion channel-forming peptidβs 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. Vfhen 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 rod-like structure.

-2- In general, such peptides have at least 7 amino acids, and preferably at least 20 amino acids. In most cases, such peptides do not have in excess of 40 amino acids.

The peptide or protein is generally employed in the form of an oral composition for oral hygiene. Such an oral composition may be incorporated into a wide variety of compositions and materials used for oral hygiene purposes, which include, but are not limited to, toothpastes, mouthwashes, tooth gels, and tooth powders. Such a compositon may thus be used to treat or prevent periodontal disease, to prevent or reduce plaque, and/or to prevent or treat or reduce dental caries. The peptide or protein thus may be used to inhibit, prevent, or destroy the growth of bacteria associated with plaque, periodontal disease, dental caries, and other dental or oral diseases or conditions. Such bacteria include, but are not limited to Streptococcus mutans. Actinobacillus ac inomvcetemcomitans. Eikenella corrodens. Streptococcus salivarius. Actinomvces naeslundii. Streptococcus sanguis. Actinomvces viscosus. Veilloπellβ species, Campylobacteria species such as Campylobacter sputorum. Bacteroides gingivalis. Capnocytophaga species such as Capnocvtophaga gingivalis. Wolinella recta, Bacteroides intermedius. Mycoplaama species such as Hycoplasma salivarium. Trepone a species, such as Treponema denticola. Peptoatreptococcus micros, Bacteroides

-3- forsythus, Fusobacteria species such as Fusobacterium nucleatum, selenomonads such as Selenomoπas sputlgena. and Bacteroides fragilis. The peptides, may also be employed in inhibiting, preventing, or destroying the growth of Enterobacter cloacae, which is associated with dental implant infections, such as periimplantitis. The peptides may also be used to inhibit, prevent, or destroy the growth of viruses which adversely affect the oral cavity, and of virally-infected cells found in the oral cavity.

The peptides may also be employed to prevent, inhibit, or destroy the growth of fungi in the oral cavity. For example, the peptides may be employed to prevent, inhibit, or destroy the growth of the fungus Candida albicans. which is associated with thrush.

The peptides may also be employed in promoting or stimulating the healing of wounds in the oral cavity.

The term "wound healing" as used herein includes various aspects of the wound healing process.

These aspects include, but are not limited to, increased contraction of wounds in the oral cavity, increased deposition of connective tissue, as evidenced by, for example, increased deposition of collagen in the wound, and increased tensile strength of the wound; i.e., the peptides increase wound breaking strength. The peptides may also reverse the inhibition of wound healing caused by a depressed or compromised immune system.

-4- In general, the peptide or protein is administered topically in an amount of from about 2 mg/ml to about 20 mg/ml.

In accordance with a preferred embodiment, the peptide is a basic (positively charged) polypeptide having at least sixteen amino acids wherein the pol^ypeptide 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 aeida) 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

-5- 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, lie, 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, Gin, Ser, and Thr. The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, hoaoarginine (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 a preferred 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.

-6- 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, in a preferred embodiment, the biologically active polypeptide comprises 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

-7- 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:

(X_)_a(A-B-C-D)_n(Y_)_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 X. is D; C-D- or B-C-D-, Y. is -A or -A-B or

-A-B-C

X₂ is A-, D-A- or C-D-A- _£ is -B, -B-C or B-C-D ₃is B-, A-B-, D-A-B-

Y₃ is -C, -C-D, -C-D-A

X₄is C-, B-C-, A-B-C-

Y₄ is -D, -D-A, -D-A-B a is o or 1; b is o 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 characteristi s of the chain to that which is significant y different from one in

-8- which the hereinabove noted group of four amino acids are not spaced from each other.

As representative examples of peptides in accordance with the present invention, there may be mentioned.

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

(SEQ ID N0:1)

II Ala-Phe-Ser-Lyβ-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 Phe-Ser-Lys-Ala-Phe-Ser- Lys-Ala-Phe-Ser-Lys-Ala- Phe-Ser-Lys-Ala- (SEQ ID NO:3)

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

V Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-I.ys-Λla-Phe-Ser- ys-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

-9- 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.

The peptides may be produced by known techniques and obtained in substantially pure form. For example, the peptides may be synthesized on an automatic synthesizer. Journal of American Chemical Society, Vol. 85 Pages 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.

In accordance with another preferred embodiment, the peptide may be a againin 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 X._

^{"" R}ir^Rir^R12^"R13^"RU^"R14^"R12^'Ri

^R ₁4"^R ₁2'^R _ll"^R _ll"^Rir^R14a^"(R15⁾n^"R14a^"R14 ^"

-10- wherein R.. is a hydrophobic amino acid, R is a basic hydrophilic amino acid; R₁₃ is a hydrophobic, neutral hydrophilic, or basic hydrophilic amino acid; R and R,- are hydrophobic or basic hydrophilic amino acids; R.. 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, R._ is a hydrophobic or neutral hydrophilic amino acid, R.. is a hydrophobic amino acid, and R._ is glutamic acid or aspartic acid.

Thus, for example, a magainin peptide may include the following structure:

^"Y12^"X12^" where X._ is the hereinabove described basic peptide structure and Y.. is

wherein X.. is as previously defined and Z._ is: (i) R._fi where R-, is a basic hydrophilic amino acid or asparagine or glutamine.

^■11- (ii) R ,-R _ where R _η is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid. Preferably, R._ is a neutral hydrophilic amino acid.

A magainin peptide may also have the following structure:

(Y ) -^X12^"^^Z12'⁾ ^lI12 a b

where X.., Y._ and Z-_ 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 X._:

^"R14^"Rir^Rl4a^'R12^"Rir^Rll^"R12^"R13^' ^Ri ^R14^"R12^"Rll^'Rll^"R12^"' ^{wherein R}H'^R12^,R13' ^R14' ^and

R,14.a are amino acids as hereinabove described.

The magainin peptide may also include the following structure X,_-Z,_; wherein X,, is the hereinabove 13 13' 13 described basic peptide structure and 7... is

^CRπV^(RllV^(RllV^(R14aV^(R15V^(R14aV^(R14V- ^{Whβrβ n R}ll^{« R}14' ^R14a' ^R15' ^R16' " ^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

-12- 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 N0:6) (OH) or NH₂) (Hagainin I)

(b) (SEQ ID NO:7) (OH) or ( H₂ (Magainin II)

(c) (SEQ ID N0:8) (OH) or (NH.) (Magainin III)

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

(d) (SEQ ID NO: ) (OH) or NH₂)

(e) (SEQ ID NO:10) (OH) or NH₂)

(f) (SEQ ID NO:11) (OH) or (NH_j)

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.

-13- A PGLa peptide is either PGLa or an analogue or derivative thereof. The PGLa peptides preferably include the following basic peptide structure X , :

^{' R}n^"R17^'R12^"Rll^"R14^"R14^"Ri

^Rιι^"Ri4^"Ri2^"Rπ^"Rιι^"Ri2^'Rι where R. . , R. _ , R, » , and R_ ₇ 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 X., is as previously defined and

^Y14 ⁱ⁸

(i) R_u;

(ii) R_1A-R_n where R.. and R-₄ 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_j4 is:

(i) R_n; or

■14- ( ii) R. . -R- - where R is as previously defined.

A PGLa peptide may also have the following structure:

(Y _. ^"X14^"^^Z14-¹ 14'a ^λ b

where X..; ., and Z., 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 X.,:

^"Rir^R17^"R12^"Rπ^"R14^"R18^"R17^" ^Rι ^Ri4^"Ri2^"Rι ^Rπ^"Ri2^" ^RI ^RI ^Rι ^Ri2-^(Ri5⁾n-^Rn^"' ^whβrβ±n

R._j, R_j_, R.,, R._ and R_j_ are as previously defined and R,_g is glutamine or asparagine or a basic hydrophilic, or hydrophobic amino acid and, n is 0 or 1.

The XPF peptides generally include βt 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 X_j, is as previously defined and Y _g is

-15- where R„1,1 and R,14, are as previously defined.

An XPF peptide may include the following structure:

where X.,, Y., and Z., 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; Andrew et al, J. Biochem. 149:531-535, 1985; Gibson et al J. Biol. Chem. 261:5341-5349, 1986; and Giovanninl et al, Biochem J. 243:113-120, 1987.

-16- In accordance with yet another embodiment, the peptide may be a CPF peptide or appropriate analogue or derviative 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 X..:

^"R2 ^R2 ^R22^"R22^"R2 ^R2l^"R23^"R2

^"R2 ^R2 ^R23^'R2 ^R2 ^R24^"R25^"R2l^" wherein R_. is a hydrophobic amino acid;

R_. is a hydrophobic amino acid or a basic hydrophilic amino acid;

R__ is a basic hydrophilic amino acid;

R_, is a hydrophobic or neutral hydrophilic amino acid; and

R_, is a basic or neutral hydrophilic amino acid.

The hereinabove basic structure is hereinafter symbolically indicated as X...

The hydrophobic amino acids are Ala, Cys, Phe, Gly, lie, Leu, Met, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohβxylalanine (Cha).

The neutral hydrophilic amino acids are Asn, Gin, Ser, and Thr.

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

-17- 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 ^{" X}20 ^" wherein X__ ia the hereinabove described basic peptide structure and Y__ is

Glyclne - R₂1~^R22~^R25" wherein R_., R„ and R__ 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 ^{" Z}20 ^Mhβreln

-18- X is the hereinabove defined basic peptide structure

wherein X₂_, Y__ and Z_2Q 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)

-19- (SEQ ID NO: 20)

(SEQ ID NO: 21)

(SEQ ID NO: 22)

(SEQ ID NO: 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.V., 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 X__ wherein:

^X31 ^{iS "{R}3l^"R32^"R32^"R33^"R3l^'R32^"R32^1"n ^X32 ^{i8 "fR}32^"R32^'R33^"R3l^"R32^"R32^'R31^]"n ^X33 ^{i8 "fR}32^"R33^"R3l^"R32^"R32^"R3r^R32^1"n ^X34 ^{is "tR}33^"R3l^'R32^"R32^"R3l^"R32^"R32-^"n ^X35 ^{i8 "fR}3l^"R32^"R32^"R3l^"R32^"R32^"R33^1"n and

^X36 ^{is ■IR}32^-R32^"R3l^'R32^"R32^"R33^"R31^,"n ^X37 ^{is "[R}32^"R3l^"R32^"R32^"R33^"R3l^'R32^I"n wherein ._} is a basic hydrophilic amino acid, R__ is a hydrophobic amino acid, R._ is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.

-20- 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, lie, 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, Gin, Ser and Thr.

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

Y_.-X_., wherein X,- is as hereinabove described, and Y__j is:

(i) R₃₂;

(ii) R₃₂-R₃₂;

(iii) R₃₁-R₃₂-R₃₂;

(iv) R₃₃-R₃₁-R₃₂-R₃₂;

(v) R₃₂-R₃₃"R₃₁-R₃₂-R₃₂; or

(vi) ^R ₃₂-R₃₂"R₃₃"R₃₁"R₃₂"^R ₃₂- wherein R._j, R^, and R,_ are as hereinabove described

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

X-.-Z,., wherein X.. is as hereinabove described, and Z._j is

-21- ( i) R₃₁ ;

(ii) R₃₁-R₃₂;

(iϋ) R₃₁-R₃₂-R₃₂;

⁽iv) R₃₁-R₃₂-R₃₂-R₃₃ ;

⁽v⁾ R₃ ^R ₃₂-^R32-^R33-^R31^: °^r ⁽vi⁾ R₃₁-R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-

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

(Y_{31 fl}-X₃₁- Z_{31 b}, wherein Y_3χ and Z₃- are as previously defined, a is 0 or 1, and b is 0 or 1.

When the peptide includes the structure X,-, the peptide may include the following structure:

Y__ - X,_, wherein X-_ is as hereinabove described, and Y_. is:

(i) R₃₁; (ii) R₃₂-R₃₁;

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

(v) R₃₃-^R ₃ ^R32-^R32^" 31^; °^r

(vi) R₃₂-R₃₃-R₃₁-R₃₂-R₃₂-^R ₃₁-

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

^X32 " ^Z32' ^{whβrβ n X} ₃₂ ^{is as} hereinabove described, and Z._ is:

(i) R₃₂;

(ii) R₃₂-R₃₂;

-22- ⁽ill⁾ R₃₂-R₃₂-R₃₃ ;

⁽ iv) R₃₂-R₃₂-R₃₃-R₃₁ ;

(v⁾ R₃₂-R₃₂;R₃₃-R₃₁-R₃₂; °r

⁽vi⁾ R₃₂-R₃₂-R₃₃-R₃₁-R₃₂-^R ₃₂ *

^^Y32'⁾a ^{" X}32 ^" ^^Z32^b' ^{wherein Y} ₃₂ ^{and z} ₃ ^{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 X__, the peptide may include the following structure:

Y__ - X-- wherein X₃₃ is as hereinabove described, and Y is:

(i) R₃₂; (ii) R₃₁- ₃₂;

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

^{(v R}3l^"R32^"R32-^R3r^R32^{; or}

(vi) ^R ₃₃-R₃₁"R₃₂"^R ₃₂"^R ₃₁"^R ₃₂' wherein R_3J, R₃₂, and R,_ are as hereinabove described.

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

X__ - Z__ wherein X^'__ is as hereinabove described, and Z_₃ is:

(i) R₃₂;

(ii) ₃₂-R₃₃;

-23-

(v) ^R32^"R33^"R3l^"R32^_R32*^' °^r

(vi) ^R ₃₂- ₃₃- ₃₁-^R ₃₂-^R3₂-^R3i-

^(Y33^}a ^{" X}33 ^{■ (Z}33V ^Whβ"^{±n Y}33 ^{βnd Z}33 "^{e 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 X_, , the peptide may include the following structure:

Y3-4, - X3_4,,' wherein X3„4, is as hereinabove described,

(iv) R₃₂-R₃₁-R₃₂-R₃₂;

(^y) ^R ₃₂- ₃₂-R₃₁-^R32-^R32^{; or}

(vi) ₃₁-^R ₃₂-R₃₂- ₃₁- ₃₂-^R ₃₂. «^h«---^{in R}3l- ^R ₃₂ ^βnd R__ are as hereinabove described.

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

X-.-Z,,, wherein X,, is as hereinabove described, 34 34' 34

(i) R₃₃;

-24- ( ii) R₃₃-R₃₁ ; ( iii) ^R ₃₃-R₃₁-R₃₂; ^{iv R}33-^R31-^R32-^R 2⁵

(v) R₃₃- ₃₁-R₃₂-^R ₃₂-^R ₃₁; or

^{(V1 R}33-^R ₃ ^R32-^R32-^R3 ^R32^" In accordance with yet another embodiment, the peptide may include the following structure:

^(Y34^}a^{" X}34^{" (Z}34⁾b' ^{whβrβln X}34 ^{and Z} ₃4 ^{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 X__, the peptide may include the following structure:

Y.--X.-, wherein X__ is as hereinabove described, and Y,_ is:

(i) R₃₃;

(ii) R₃₂-R₃₃;

(iii) R₃₂-R₃₂-R₃₃;

(iv) R₃₁-R₃₂-R₃₂-^R ₃₃;

^{(V) R}32-^R3 ^R32^"R32-^R33^{; or} (vi) ^R ₃₂-^R ₃₂- ₃₁-^R ₃₂- ₃₂- ₃₃. »"««*" ^R ₃r ^R32» ""* R._ are as hereinabove described.

-In accordance with another embodiment, when the peptide includes the structure X,_, the peptide may include the following structure:

X_, - Z_« wherein X_« is as hereinabove described, and Z_, is:

(i) -₃₁,

-25- ( ii) R_{3 -} -R₃₂;

⁽iii) R₃₁-R₃₂-R₃₂. ⁽iv^{) R} ₃₁-R₃₂-R₃₂-R₃₁;

^(y) R₃ R₃₂-R₃₂-R₃ ^R32^{: or} ⁽vi^{) R} ₃₁-R₃₂-R₃₂-R₃₁-^R ₃₂-^R ₃₂-

(Y_«) - X₃₅ (Z₃_ _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 X,_fi, the peptide may include the following structure:

Y_, - X_, wherein X-, is as hereinabove described, and Y₃₆ is:

(i) R₃₁; (Ii) R₃₃-R₃.;

(iii) R₃₂-R₃₃-R₃₁s

(iv) R₃₂-R₃₂-R₃₃-R₃₁;

(v) ^R31^"R32^"R32^"R33^"R31^; °^r

(vi) ^R ₃₂ ^_R ₃₁"^R ₃₂"^R ₃₂-^R ₃₃"^R ₃₁' wherein R₂₁ , R and R,_ are as hereinabove described.

^X36*^Z36_* ^{whβrβin X}3_β ^{is as} hereinabove described, and Z is:

-26- ( ii) R₃₂-R₃₂; ( iii) R₃₂-R₃₂-^R ₃₁ ; ⁽ iv⁾ R₃₂-R₃₂-R₃₁-R₃₂; (v) ₃₂-^R ₃₂-R₃₁-^R ₃₂-^R ₃₂; or

(vi) ₃₂-^R ₃2^_R ₃ ^R32^"R32^"R33" In accordance with yet another embodiment, the peptide may include the following structure:

^(Y3βV ^X36 ^(Z36 ^{Whβrβin Y}36 ^{βnd Z}36 ^are " previously defined, a is 0 or 1, and b is 0 or 1.

In accordance with one embodiment, when the peptide includes the structure X,_, the peptide may includes the structure Y,_-X,_, wherein X,_ is as hereinabove described, and Y__ is:

⁽i) ^R ₃₂;

⁽ii) ^R ₃₁-R₃₂;

(iii) R₃₃-R₃₁-R₃₂;

(iv) R₃₂-R₃₃-R₃₁-R₃₂;

(v) R₃₂-^R ₃₂-R₃₃- ₃₁- ₃₂; or

(vi) ^R ₃₁-^R ₃₂-R₃₂ ^_R ₃₃ ^-R ₃₁"^R ₃₂» wherein R_31> R_32> and R-, are as hereinabove described.

In accordance with a further embodiment, when the peptide includes the structure X₃-, the peptide may include the following structure:

X₃- - Z₃_ wherein X„ is as hereinabove described, and Z__ is:

(i^{) R} ₃₂;

(ii) R₃₂-R₃₁;

-27- (iii⁾ R₃₂-^R ₃₁-R₃₂;

⁽iv⁾ R₃₂-R₃₁-R₃₂-R₃₂;

⁽v⁾ R₃₂-R₃₁-R₃₂-R₃₂-R₃₃ ; or

⁽vi^{) R} ₃₂-^R ₃₁-^R ₃₂-^R ₃₂-^R ₃₃-^R ₃₁ -

(Y„)_a- X₃₇ Z„ _b, wherein Y₃₇ and Z„. 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 He Ala Gly Lys He Ala)₃ (SEQ ID NO:27).

(Lys He Ala Lys He Ala Gly)₃ (SEQ ID NO:28).

(Lys He Ala Gly Lys He 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 N0:31).

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

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

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

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

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

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

(Lys Phe Ala Arg He Ala Gly)₃ (SEQ ID NO:38).

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

(Lys He Ala Gly Orn He Ala)_ (SEQ ID N0:40).

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

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

-28- (Gly He Ala Arg He Phe Lys). (SEQ ID NO: 3). (Lys Nle Ala Gly Lys Nle Ala) (SEQ ID NO:44). (Lys Nle Ala Gly Lys He Ala). (SEQ ID NO:45). (Lys He Ala Gly Lys Nle Ala)₃ (SEQ ID N0:46). (Lys Nva Ala Gly Lys Nva Ala)₃ (SEQ ID NO:47). (Lys Nva Ala Gly Lys He Ala)₃ (SEQ ID NO:48). (Lys Leu Leu Ser Lys Leu Gly), (SEQ ID NO.-49). (Lys Leu Leu Ser Lys Phe Gly). (SEQ ID NO:50). (Lys He Ala Gly Lys Nva Ala)₃ (SEQ ID NO:51). (His He Ala Gly His He Ala). (SEQ ID NO:52). (Ala Gly Lys He Ala Lys Ile)₃ (SEQ ID NO.-53). (He Ala Lys He Ala Gly Lys)₃ (SEQ ID NO:54). (Lys He Ala Gly Arg He Alα)₃ (SEQ ID NO:55). (Arg He Al Gly Arg He Ala). (SEQ ID NO:56). (Lys Vαl Ala Gly Lys He Ala). (SEQ ID NO:57). (Lys He Ala Gly Lys Val Ala). (SEQ ID NO:58). (Al Lys He Ala Gly Lys lie). (SEQ ID NO:59). (Orn He Ala Gly Orn He Ala)₃ (SEQ ID NO:60). (Lys Phe Ala Gly Lys He Ala). (SEQ ID NO:61). (Lys He Ala Gly Lys Phe Ala). (SEQ ID NO:62). (Lys Cha Ala Gly Lys He Ala). (SEQ ID NO:63). (Lys Nle Ala Lys He Ala Gly). (SEQ ID NO:64). (Arg He Ala Gly Lys He Ala). (SEQ ID NO:65). (Har He Ala Gly Har He Ala)₃ (SEQ ID NO:66). (Xaa He Ala Gly Lys He Ala)₃ (SEQ ID NO:67). (Lys He Ala Gly Xaa He Ala), (SEQ ID NO:68).

-29- Lys He Ala (Lys He Ala Gly Lys He Ala) (SEQ ID NO:69).

In (SEQ ID N0:67) and (SEQ ID NO:68), Xaa is p-aminophβπylalanine.

In accordance with another embodiment, the biologically active amphiphilic peptide includes the following basic structure X,_:

^R3 ^R32^"R32^'R33^"R34^"R32^"R32^'R3 ^R32^"R32^"R32^"R34^"R32^"R32' wherein R_., R__, and R are as hereinabove described, and R_, is a basic hydrophilic or hydrophobic amino acid.

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

Y4_/«0-X4_/rt0- wherein X4,„0 is as hereinabove described,

(iv) R₃₃-R_3A-R₃₂-R₃₂;

(v) ^R32^"R33^"R34^'R32^"R32^:

(^y R₃₂-^R32-^R33-^R3 -^R32-^R32' °^r

(vii) ^R ₃₁- ₃₂-R₃₂-R₃₃-R₃₄-^R ₃₂-^R3₂.»herein R_31> R^,

^R33 ^{and R}34 are as hereinabove described.

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

-30- ^X4_θ" 4_θ - "herein X, . is as hereinabove described and

Z 4, _n0 is:

⁽ i⁾ ₃₁ ⁽ ϋ) R₃₁-R₃₂; ⁽ iii⁾ R₃₁-R₃₂-R₃₂; ⁽ iv) ^R ₃₁-R₃₂-R₃₂-R₃₃; (v) ^R ₃₁-^R ₃₂-R₃₂-R₃₃-R₃₄;

⁽vi^{) R} ₃Γ^R _{32 32}- ₃₃-^R ₃₄-^R3 J ^or

(vii) ^R ₃₁-^R ₃₂-R₃₂-R₃₃-R₃4-R₃₂-R₃₂. "herein R.,., R₃₂, R,,, and R_, are as hereinabove described.

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

^(Y4θY^X4θ^"(Z4θV ^{whβrβln Y}40 ^{and Z}40 ^β" " 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)

-31- (SEQ ID NO:74) (SEQ ID NO:75) (SEQ ID NO: 6) (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:

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

(Lys He Ala Lys Lys He Ala)₃ (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:

-32- (Lys Phe Ala Lys Lys Phe Ala). (SEQ ID N0:89)

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

(Lys Phe Ala Lys Lys He 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 sarcσtoxin.

The term cecropins includes the basic structure as well as analogues and derivatives thpreof. 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.

-33- 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 X₍-_π'

^R4l^"R42^"R42^"R4l^"R42^"R42^"R4l^"R4r^R42^-R4l^"R41-

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

In one embodiment, the peptide includes the basic structure Y_ -X_. wherein X-₀ is as hereinabove described and Y_₀ is:

C R₄₁;

(ii) R₄₂-R₄₁; or

(iii) ^R ₄2"^R ₂"^R ₄ι» wherein R,_j and R-₂ are as hereinabove described.

In one embodiment, R,. is leitcine. In another embodiment, R,_ 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)

-34- In accordance with another embodiment, the amphiphilic peptide includes the following basic structure X__:

^R42^"R4 ^R 2^'R42^"R4r^R r^R 2^"R 2^"R r^R 2~^R 2' ^wherein R,. is a hydrophobic amino acid and R,_ is a basic hydrophilic or neutral hydrophilic amino acid.

In one embodiment R 4, ,1 is leucine. In another embodiment, R,„ is lysine.

In one embodiment, the peptide includes the basic is as hereinabove

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)

-35- In another embodiment, the peptide includes the basic structure X_. - Z_., wherein X_ is as hereinabove described, and Z_. is:

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:

^CT52^Ja ^{" X}52 ^{■ (Z}52V ^whe"^{in X}52' ^Y52 ^{and Z}52 ^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_,:

^"R4I^"R42^"R42^"R4 ^R4I^'R42^_R42^"R4Γ^R42^"R42^"R4 ^R4 ^R42^"R42^"

^R43' wherein R, , and R,„ are as hereinabove described, and R.. 41 42 43 is a natural hydrophilic amino acid.

•36- 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 X.,:

^R4r^R42^"R4 ^R4l^"R42^"R42^"R4r^R4r^R42^"R42^"R44' ^whβ"i" R₄₁ and R,_ are as hereinabove described, and R, , is a neutral hydrophilic amino acid or proline.

In one embodiment, the peptide may include the following structure Y₅₆"^χ _e6» wherein X_, is the basic peptide structure hereinabove described, and Y_, is:

wherein R, , and R,_ are as hereinabove described. 41 42

In one embodiment, the peptide may include the structure:

X.,-Z__g, wherein X_, is as hereinabove described, and

56 is:

(i) 42^»

-37-

(v) ^■R42~^R42^"R41-^R4r^R42^; (vi) -^R4₂-^R4₂- 4₁ ^R 2-^R 2^: °^r (vii) -^R4₂-^R4₂-^R4l-^{R R} 2^_R42^"R 1" 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 ςg _fl"^X56"f^Z5fi)b' ^{wherein X}5fi» ^Y56' ^{and Z}5 ^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 X__:

^R41~^R4l^'R42^'R42^"R4l^"R42^"R42^"R4l^"R4l^"R42^"R42^"R4 ^R43' wherein R, , , R,_ and R,, are as hereinabove described. 41 42 43

In accordance with another embodiment, the peptide may include the structure ^ς_o'^_ςg- wherein X, is as hereinabove described, and Y_. is:

or

-38- (vii) -^R42-^R 2-^R l r^R 2-^R42-^R 1 ' "herein R₄₁ and R,, are as hereinabove described.

42

In another embodiment, the peptide includes the structure X,_-Z__, wherein X,_g is as hereinabove described, and Z_ is:

(ii) -^R ₄₁- ₄₅; (iii) -R₄₁-R₄₅-R_45;

(iv) -R₄₁- ₄₅-R₄₅.R₄₃;

(v) -R₄₁-R_4S-R₄₅_R₄₃-R₄₁

(vi) -R₄₁-R₄₅-R₄₅_R₄₃-R₄₁-R₄₃;

(vii) -R₄₁-R₄₅-R₄₅__>R₄₃-R₄₁-R₄₃-R₄₃,

(viii) -R₄₁-R_4S-R_4S.R₄₃-R₄₁-R₄₃-R₄₃- ₄₅; or

(ix) -R₄₁- ₄₅-R₄₅_R₄₃-R₄₁-R₄₃-R₄₃-R₄₅-R₄₃, wherein R. , and R,, are as hereinabove described, and R,, 41 43 45 is proline.

In one embodiment, the peptide has the following structure:

(SEQ ID NO:105).

In one embodiment, the peptide may have the structure

^{whβrβin X}58^{» Y}5B^{« βnd Z}58 ^are " 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 X,_;

^R4 ^R4 ^R43^"R42^"R4 ^R4 ^{R R}41^"R41^"R4 ^R42^"R4 ^R4 ^R42^"" ^R42^"R4l^"

-39- ^R4 ^R42^"R42^"R42~^R41' ^{whereiπ R}41' ^R42' ^a"^{d R}43 ^{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 ^xgn"^Z60' wherein X.. is as hereinabove described, and Z,_ is:

^{(a R}4 ^R42^"R42^"R4l^"R- ^"R42^"R4r

(b) ^R ₄₁- ₄₁- ₄₂-^R ₄₂-^R ₄₁-^R ₄₂-R₄₂-^R4₁;

(c) ₄₂-R₄₁-R₄₁-R ₂-R₄₂-R ₁-^R4₂-^R4₂-^R4₁;

(d) R₄₂-R₄₂-R₄₁-R₄₁-R₄₂-R₄₂- _4]-^R ₂-^R4₂-^R4₁; ∞d

(e) R₄₁-R₄₂-R₄₂- ₄₁-R ₁-R₄₂-R4₂-^R ₁-^R ₄₂-^R ₂-^R ₁. wherein R,, and R,„ are as hereinabove described. 41 42

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.

-40- 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 Habβrmann, et αl., Hoppe-Seyler's Zeitschrift Physiol. Chem.. Vol. 348, pgs. 37-50 (1987). Melittin

-41- has the following structural formula as represented by the three-letter amino acid code: Gly He Gly Ala Val Leu Lys Val Leu

5 Thr Thr Gly Leu Pro Ala Leu He Ser 10 15

Trp He Lys Arg Lys Arg Gin Gin

20 25

(SEQ ID NO:114)

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

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 neutrophll 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,

-42- 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. Exp. 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.

In accordance with yet another embodiment, each of the amino acid residues of the peptide or protein may be a D-amino acid residue or glycine.

It is also to be understood that the peptides or proteins may be administered in combination with one another.

In accordance with another embodiment, the peptides or proteins of the present invention may be employed in combination with an ion having pharmacological properties for the purposes hereinabove described.

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

-43- 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, actives and/or inactives, in addition to the peptide or protein and anti-target ion. As representative examples of ions having pharmacological properties which may be employed, there may be mentioned fluoride, peroxide, bicarbonate, silver, zinc, mercury, arsenic, copper, platinum, antimony, gold, thallium, nickel, selenium, bismuth, and cadmium ions. In one embodiment, the ion having pharamacological properties is a fluoride ion.

The peptide or protein and the 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 oral bacteria, or of viruses or fungi which adversely affect the oral cavity. In effect, the ion potentiates the action of the peptide or protein, i.e., the amount of ion is effective to reduce the minimum effective concentration of the peptide or protein for inhibiting growth of oral bacteria, fungi, viruses, or

-44- virally-infected cells which adversely affect the oral cavity.

The ion having pharmacological properties is generally employed in a concentration of from about 1 mg/ml to about 10 mg/ml.

As representative examples of administering the peptide or protein and ion having pharmacological properties, the peptide or protein could be administered in an amount of up to about 25 weight to weight and the ion delivered in an amount of about 0.1% to 1.0%.

It is also contemplated that, within the scope of the present invention, the peptide may be administered in combination with other oral hygiene agents such as, but not limited to, chlorhexidine (peridex), sanguinarine HCl, antiseptic mouthwashes, tricolssn, etc.

In accordance with another embodiment, the peptides or proteins of the present invention may be administered to a host in combination with an antibiotic selected from the class consisting of bacitracins, gramacidins, polymyxin, vancomycin, teichoplanin, aminαglycosides, hydrophobic antibiotics, penici... --onobactams, or derivatives or analogues thereof.

The bacitracins, gramacidins, polymyxin, vancomycin, and teichoplanin, and derivatives - -liogues thereof, are a group of polypeptide antibiotics. A preferred bacitracin is bacitracin A.

-45- Amino lycoside antibiotics include tobramycin, kanamycin, amikacin, the geπtamicins (e.g., gentamicin C., gentamicin C_, gentamicin C ), netilmicin, kanamycin, and derivatives and analogues thereof. The preferred aminoglycosides are tobramycin and the gentamicins. The aminoglycosides, and the bacitracins hereinabove described, tend to be hydrophilic and water-soluble.

Penicillins which may be employed include, but are not limited to benzyl penicillin, amplcillin, methiclllln (dimethoxyphenyl penicillin), ticβricillin, penicillin V (phenoxy ethyl penicillin), oxacillin, cloxacillin, dicloxαcillln, flucloxacillin, amoxicillln, and amidinocillln. Preferred penicillins which may be employed are benzyl penicillin and amplcillin. A preferred monobacta which may be employed is aztreonam.

As representative examples of hydrophobic antibiotics which may be used in the present invention, there may be mentioned macrolides such as erythromyein, roxythromycin, clarithromycin, etc. ; 9-N-alkyl derivatives of erythromyein; midecamycin acetate; azithromycin; flurithromycin; rifβbutin; rokitamycin; a 6-0-raβthyl erythromyein A known as TE-031 (Taisho); rifapentine; benzypiperazinyl rifβmycins such as CGP-7040, CGP-5909, CGP-279353 (Ciba-Geigy); an erythromyein A derivative with a cyclic carbamate fused to the C../C-. position of a macrolide ring known as

-46- A-62514 (Abbott); AC-7230 (Toyo Jozo); benzoxazinorifamycin; difficidin; dirithromycin; a 3-N-piperdinomethylzaino methyl rifamycin SV known as FCE-22250 (Farmitalia); M-119-a (Kirin Brewery); a 6-0-methyl-l-4"-0-carbamoyl erythromyein known as A-63075 (Abbott); 3-formylrifamycin SV-hydrazones with diazabicycloalkyl side chains such as CGP-27557 and CGP-2986 (Ciba-Geigy); and 16-membered macrolides having a 3-0-alpha-L-cladinosyl moiety, such as 3-0-alpha-L-cladinosyldeepoxy rosαramicin; tylosins and acyl demycinosyl tylosins.

In addition to the macrolides hereinabove described, rifamycin, carbenicillin, and nafcillin may be employed as well.

Other antibiotics which may be used (whether or not hydrophobic) are antibiotics which are 50-S rlbosome inhibitors such as lincomycin; cUndamycin; and chloramphβnicol; etc.; antibiotics which have a large lipid like 1actone ring, such as mystatin; pimaricin, etc.

The peptide or protein and antibiotic may be adminstered orally In order to prevent, destroy or inhibit the growth of bacteria, such as but not limited to those hereinabove described, which may be associated with adverse oral conditions. Bacteria whose growth may be prevented, inhibited, or destroyed by the

-47- administration of the peptides and antibiotic include Gram-positive and Gram-negative bacteria.

The antibiotic, such as those hereinabove described, or derivatives or analogues thereof, is generally employed in a concetration of about 0.2% to about 2.0%. Peptide or protein dosages may be those as hereinabove described.

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

In the following Examples 1 through 5, the antibacterial activity of various peptides within the scope of the present invention was measured against various oral bacteria by a modification of the Kirby-Bauer technique (Bauer, et al., Am. J. Clin. Path.. Vol. 36, No. 3 (1966), pgs. 493-496) In which growth inhibition of the organisms was measured on agar plates seeded with bacterial lawns.

The procedure for determining such growth inhibition is as follows:

A few colonies of each organism to be tested are picked up with a wire loop and introduced into a test tube containing broth. A broth containing 28g Brucella broth, 2g sodium formate, 3g sodium fumarate, 50 ml defibrinated sheep blood, 2 ml hemolyzed sheep blood cells, 10 ml herain-menadione solution, and 1 liter of distilled H.O was prepared for the following organisms:

-48- Eikenella corrodens;

Peptostreptococcus micros;

Bacteroides iπtermedius:

Bacteroides fragilis:

Bacteroides gingivalis; and

Actinomyces viscosus.

The hemin-menadione solution used in the above-described broth was prepared by dissolving 50 mg of hemin in 1 ml IN NaOH, and brought to 100 ml with distilled H₂0 to form a hemin solution. 100 mg of menadione was added to 20 ml distilled H.O to form a menadione solution. 1 ml of the menadione solution is then added to 100 ml of the hemin solution to form the hemin-menadione solution 10 ml of which is added to the broth.

A broth containing 22g trypticase soy broth, lg yeast extract, 100 ml horse serum, 5 ml of a bacitracin solution of 75 mg bacitracin in 5 ml distilled H.0, 5 ml of a vancomycin solution of 5 mg vancomycin in 5 ml distilled H₂0, and 1 liter of distilled 1 0 is prepared for Actinobacillus actinomycetemcomitans. A broth containing 37g brain heart infusion, lOg yeast extract, 2g sodium formate, 3g sodium fumarate, 0.3g sodium thiosulfate, 0.2g ferrous sulfate, 5 ml of a hemin-menadione solution of 2.5 tng/1 hemin and 0.25 mg/1 menadione, a solution of 9 mg vancomycin in 12 ml

-49- distilled water, and 1 liter of distil led H,0 was

_ prepared for Wolinella recta.

The tubes are incubated to produce a bacterial suspension of moderate cloudiness. The bacteria-containing broth is then diluted, If necessary, with water or saline solution to a density virtually equivalent to that of a 0.5 McFarland standard prepared by adding 0.5 ml' of 1% BaCl, to 99.5 ml of 1% H„S0,

2. 2 4

(0.36N).

The bacterial broth suspension is streaked evenly in three planes onto the surface of the culture medium of 5 to 6 mm in depth, in a Petri dish, with a cotton swab. An agar medium of 3.0% tryptlease soy broth, 1.5% agarose, 2.5 mg/1 hemin, and 0.25 mg/1 menadione is used for the following organisms: Eikenella corrodens: Peptostreptococcus micros; Bacteroides gingivalis; Bacteroides fragilis; Bacteroides intermedius; and Actinomvces viscosus; and Actinobaeillus actinomycetemeomitans. A medium containing 52g brain heart „infusion, agarose, lOg yeast extract, 2g sodium formate, 3g sodium fumarate, 5 ml of a hemin-menadione solution of 2.5 mg/1 hemin and 0.25 mg/1 menadione, and 9 mg vancomycin in 12

-50- ml distilled H.O, 0.3g sodium thiosulfate, and 0.2g ferrous sulfate was used for Wolinella recta.

After the inoculum has dried, but no longer than 15 minutes after drying, disks saturated with peptide or peptide and NaF are placed on the agar with flamed forceps or a disk applicator. The disks have been saturated with 20 μl of a peptide solution to deliver a final dose of from 0.25 μg to 128 μg on the disk or with peptide in the heretofore mentioned dosages and 1,000 ppm NaF. The disks may be laid down in a circle to form an outer ring of about 9 disks, and the remaining disks may be placed in the center.

After overnight incubation, the zone diameters (including the 6mm disk) are measured on the undersurface of the Petri disk with a ruler or with calipers near the agar surface. A reading of 6mm indicates no inhibition. The end point is taken as the lowest dose causing inhibition of growth as determined by the naked eye.

Example 1

In this example, Peptides 1 through 4 were tested for the minimal inhibitory concentration (MIC) against A. actinomycetemcomitans strain Y4, Eikene11a corrodens. S. mutans strain 6714, S. san ius strain M-5, and A. viscosus strain T14V. Peptide 1 has the following structural formula:

(SEQ ID NO:115)

Peptide 2 has the following structural formula:

-51- (SEQ ID NO: 12)

Peptide 3 has the following structural formula: (SEQ ID NO: 116)

Peptide 4 has the following structural formula: (SEQ ID NO:117)

The results are given below in Table I.

Table I MIC (μg/ml) Or anism Pe tide 1 Pe tide 2 Pe tide 3 Pe tide 4

The procedure of Example 1 was repated to determine the HIC of peptides 1 through 4 against A.viscosus strain T14, S.mutans. S.sangius. A.actinomycetemcomitans strain Y4, E.corrodens. Bacteroides gingivalis, Wolinella recta strain 371, and Baeterioides intermediu . The results are given below in Table II.

-52- Table II

* resistant colonies developed.

** extremely large zone of inhibition.

Example 3 The MIC of Peptides 1 through 4 alone, and of Peptides 1 through 4 in combination with 1,000 ppm NaF was tested against A.viscosus. S.sangius strain M4, S.mutans strain 6715, E.corrodens strain 28371, A.actinomycetemcomitans strain Y4, B. ingivalis strain 33277, B.intermedius strain 25611, and W.recta strain 371. Table III gives the MIC of each peptide alone against each organism, while Table IV gives the MIC of each peptide in combination with 1,000 ppm NaF against each organism.

-53- Table III

-54- Table IV

The above results show that the MTC for the peptides were markedly decreased in the presence of 1,000 ppm NaF; i.e., there does appear to be some kind of interaction between the peptide and NaF against oral bacteria.

Example 4

In this example, peptides 1, 4, 5, 6, and 7 were tested for minimum inhibitory concentration (MIC) against Bacteroides fragilis.

Peptide 5 has the following structural formula:

(SEQ ID N0:118)NH₂.

-55- Peptide 6 has the following structural formula:

(SEQ ID N0:119)-NH₂.

Peptide 7 has the following structural formula:

(SEQ ID NO:70)NH₂.

Table V below gives the zones of inhibition at various concentrations of peptide per disc. Table V - Zones of Inhibition μg peptide/disc Peptide 0 I 1 4 ji JJ5 32 64 1 - 8mm 11mm 12mm

4 - 11mm 11mm 12mm 13mra

5 - 11mm 12mm 11mm 11mm

6 - Hram

7 - _ _ _ - _ _fflm 9.5mm

From the above table, it can be seen that the MIC of Peptide 1 is 16μg/ml, the MIC of Peptide 5 is Bμg/ml, the MIC of Peptide 6 is 64μg/ml, and the MTC of Peptide 7 is 32μg/ml.

Example 5

In this example, peptides 5, 8, 9, and 10 were tested for minimum inhibitory concentration (MIC) against the following organisms:

Bacteroides gingivalis;

Bacteroides intermedius;

Actinobacillus actinomycetemcomitans;

Eikenella corrodens;

-56- Wolinella recta;

Eπterobacter cloacae;

Actinomvces viscosus; and

Peptostreptococcus micros.

Peptide 8 has the following structural formula:

(SEQ ID NO:27)

Peptide 9 has the following structural formula:

(SEQ ID N0:120)-NH₂-

Peptide 10 has the following structural formula:

(Lys He Ala Gly Lys He Ala)., wherein each amino acid residue is a D-amino acid residue or glycine.

The MIC values for each peptide are given below in Table VI.

-57-

The above assay procedure was also followed in which chlorhexidine gluconate was tested for MIC against Enterobacter cloacae. The MIC of chlorhexidine gluconate against Enterobacter cloacae was 128μg/ml. This indicates that Enterobacter cloacae, which is similar to most of the Gram-negative organisms associated with periimplantitis, is more sensitive to the peptides hereinabove tested than it is to chlorhexidine, which is commonly employed in a rinse after denture implant surgery and placement.

Example 6 -58- In this example, saliva, with its native bacterial flora intact, is isolated from a human volunteer, and is then passed continuously over germanium crystals for 20 minutes prior to treatment. Germanium crystals have surface properties similar to tooth enamel. After equilibration of the saliva in the flow system, water, or Peptide 11, also known as (SEQ ID NO:121); Peptide 12, also known as D-(SEQ ID NO:121) (In which each amino acid residue is a D-amino acid residue or glycine); chlorhexidine; or triclosan in a concentration of O.lmg/ml in water, were applied for a period of 30 seconds, two times per day for three days. After the treatment, the germanium crystals were analyzed for bacterial count, plaque area, plaque score, and extracellular carbohydrate (ex-CHO, which is indicative of bacterial concentration), by use of a Fourier transformed infrared speetrophotometer. The results are shown in Figure 1. As shown in Figure 1, the Peptide 11 and Peptide 12 are more effective against bacteria and plaque than chlorhexidine or triclosan.

The above examples indicate that the peptides of the present invention, whether such peptides are used alone or in combination with other agents such as, for example, fluoride ions, are effective against oral bacteria associated with plaque, gingivitis, halitosis, dental caries, periodontal disease, and other adverse oral conditions.

-59- 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 practiced other than as particularly described and still be within the scope of the accompanying claims.

-60- SEQUENCE LISTING

(1) GENERAL INFORMATION:

(i) APPLICANT: Berkowitz, Barry A.

Jacob, Leonard S.

(ii) TITLE OF INVENTION: Prophylaxis and Treatment of Adverse Oral Conditions with Biologically Active Peptides.

(iii) NUMBER OF SEQUENCES: 121

(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: US/07/735,070

(B) FILING DATE: 25-JUL-1991

(C) CLASSIFICATION:

(vii) PRIOR APPLICATION DATA:

(A) APPLICATION NUMBER: 07/735,070

-61- (B) FILING DATE: 25-JUL-1991

(viii) ATTORNEY/AGENT INFORMATION:

(A) NAME: Olstein, Elliot M.

(B) REGISTRATION NUMBER: 24,025

(C) REFERENCE/DOCKET NUMBER: 421250-129(CIP)

(ix) TELECOMMUNICATION INFORMATION:

(A) TELEPHONE: 201-994-1700

(B) TELEFAX: 201-994-1744

(2) INFORMATION FOR SEQ ID NO:l:

(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

( i) SEQUENCE DESCRIPTION: SEQ ID NO:l: 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:

-62- (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

( i) 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

-63- (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 Lyε

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

-64- (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: Zaβloff, 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:6: Gly lie Gly Lys Phe Leu His Ser Ala Gly

5 10

Lys Phe Gly Lys Ala Phe Val Gly Glu He

15 20

Met Lye Ser

(2) INFORMATION FOR SEQ ID NO:7:

-65- ( 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: Zaβloff, 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

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

5 10

Lys Phe Gly Lys Ala Phe Val Gly Glu He

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

-66- (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 He Gly Lys Phe Leu His Ser Ala Lys

5 10

Lys Phe Gly Lys Ala Phe Val Gly Glu He

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

-67- (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: He Gly Lyε Phe Leu His Ser Ala Lys Lys

5 10

Phe Gly Lys Ala Phe.Val Gly Glu He 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

-68- (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: Gly Lys Phe Leu His Ser Ala Lyε Lys Phe

5 10

Gly Lyε Ala Phe Val Gly Glu He 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 He Met Asn Ser

15 20

(2) INFORMATION FOR SEQ ID NO:12:

-69- (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

•70- (Xi) SEQUENCE DESCRIPTION: SEQ ID NO:12: Gly Met Ala Ser Lys Ala Gly Ala He Ala

5 10

Gly Lys He 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:

-71- (C) JOURNAL: Biochem J.

(D) VOLUME: 243

(F) PAGES: 113-120

(G) DATE: 1987

^•72- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: Gly Trp Ala Ser Lys He Gly Gin Thr Leu

5 10

Gly Lys He Ala Lys Val Gly Leu Lys Glu

15 20

Leu He Gin 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.

-73-

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

5 10

Lys Ala Ala Leu Lys He Gly Ala Asn Ala

15 20

Leu Gly Gly Ala Pro Gin Gin

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.

-74- (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: 15: Gly Leu Ala Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Gly Leu Lys He Gly Ala His Leu

15 20

Leu Gly Gly Ala Pro Gin Gin

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

-75- (ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATION: (A) AUTHOR: Richter, K.

-76- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16:

Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu

5 10

Lys Ala Gly Leu Lys He Gly Thr His Phe

15 20

Leu Gly Gly Ala Pro Gin Gin

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.

-77- 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 He Gly Thr His Phe

15 20

Leu Gly Gly Ala Pro Gin Gin

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.

-78- (D) VOLUME: 261 . (F) PAGES: 3676-3680

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

5 10

Lys Ala Ala Leu Lys He Gly Ala Asn Met

15 20

Leu Gly Gly Thr Pro Gin Gin

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

-79- ( 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

-80- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys He Gly Ala Asn Ala

15 20

Leu Gly Gly Ala Pro Gin Gin

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. -81-

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

5 10

Lys Ala Ala Leu Lys He Gly Ala Asn Ala

15 20

Leu Gly Gly Ser Pro Gin Gin

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, . Egger, R. Kreil (C) JOURNAL: J. Biol. Chem.

-82-

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

5 10

Lys Ala Ala Leu Lys He Gly Ala Asn Leu

15 20

Leu Gly Gly Thr Pro Gin Gin

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

•83- (ii) MOLECULE TYPE: peptide

( ix ) FEATURE :

(A) NAME/KEY: CPF peptide.

(X)

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22: Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys He Gly Ala Asn Ala

15 20

Leu Gly Gly Ala Pro Gin Gin

25

-84- (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⁾

-85- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23 Gly Phe Ala Ser Phe Leu Gly Lyε Ala Leu

5 10

Lys Ala Ala Leu Lyε He Gly Ala Asn Met

15 20

Leu Gly Gly Ala Pro Gin Gin

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. -86- 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 He Gly Ala Asn Ala

15 20

Leu Gly Gly Ser Leu Gin Gin

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) VOL' HE: 261

(F) PA- ^•: 3676-3680

(G) DA!. : 1986

-87- (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 He Gly Thr Asn Phe

15 20

Leu Gly Gly Ala Pro Gin Gin

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.

-88- (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 He Gly Ala Asn Ala

15 20

Leu Gly Gly Ser Pro Gin Gin

25

(2) INFORMATION FOR SEQ ID NO:27: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

-89- (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

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

5 10

Gly Lyε He Ala Lys He Ala Gly Lys He

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 He Ala Lys He Ala Gly Lys He Ala

5 10

Lys He Ala Gly Lys He Ala Lys He 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

-90- ( Xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 29 Lys He Ala Gly Lys He Gly Lyε He Ala

5 10

Gly Lys He Gly Lys He Ala Gly Lyε He

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

-91- 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 Lyε Ala Leu Gly Lys Leu Leu

5 10

Lys Ala Leu Gly Lys Leu Leu Lys Ala Leu

15 20

Gly

-92- (2) INFORMATION FOR SEQ ID NO:34: (1) BEQUBNβS eHARAeffiRiflfϊθB

(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 He Gly Lys Ala He Lys Ala He 5 10

Gly Lyε Ala He Lys Ala He Gly Lys Ala

15 20

He

(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 He Ala Lys He Ala Lys Gly He Ala

5 10

Lys He Ala Lys Gly He Ala Lys He Ala

15 20

Lys

(2) INFORMATION FOR SEQ ID NO:36: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

-93- (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

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

5 10

Lys He Phe Gly Lys He Ala Lys He 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

( i) SEQUENCE DESCRIPTION: SEQ ID NO:37: Gly He Ala Arg He Ala Lys Gly He Ala

5 10

Arg He Ala Lys Gly He Ala Arg He Ala

15 20

Lyε

(2) INFORMATION FOR SEQ ID NO:38: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

-94- ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 38 : Lys Phe Ala Arg He Ala Gly Lys Phe Ala

5 10

Arg He Ala Gly Lys Phe Ala Arg He 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 He Ala Lys Gly Phe Ala

5 10

Lys He Ala Lys Gly Phe Ala Lys He 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

-95- ( i ) SEQUENCE DESCRIPTION: SEQ ID NO : 40 : Lys He Ala Gly Xaa He Ala Lys He Ala

5 10

Gly Xaa He Ala Lys He Ala Gly Xaa He

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:

Lyε He Ala Arg He Ala Gly Lys He Ala

5 10

Arg He Ala Gly Lys He Ala Arg He 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

-96- (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42: Xaa He Ala Gly Lyε He Ala Xaa He Ala

5 10

Gly Lys He Ala Xaa lie Ala Gly Lys He

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 He Ala Arg He Phe Lys Gly He Ala

5 10

Arg He Phe Lys Gly He Ala Arg He 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.

-97- (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Lys Xaa Ala Gly Lys Xaa Ala Lyε Xaa Ala

5 10

Gly Lyε 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: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:45: Lys Xaa Ala Gly Lye He Ala Lys Xaa Ala

5 10

Gly Lys He Ala Lys Xaa Ala Gly Lys He

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:

-98- (D) OTHER INFORMATION: Xaa is norleucine.

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

Lys He Ala Gly Lys Xaa Ala Lys He Ala

5 10

Gly Lys Xaa Ala Lyε He Ala Gly Lys Xaa

15 20

Ala

(2) INFORMATION FOR SEQ ID NO:47: (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: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

-99- (ix) FEATURE:

(D) OTHER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:48: Lys Xaa Ala Gly Lys He Ala Lys Xaa Ala

5 10

Gly Lys He Ala Lyε 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

-100- ( i) SEQUENCE DESCRIPTION: SEQ ID NO:50:

Lys Leu Leu Ser Lyε 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 He Ala Gly Lys Xaa Ala Lys He Ala

5 10

Gly Lys Xaa Ala Lys He 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

^■101- ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 52 : His He Ala Gly His He Ala His He Ala

5 10

Gly His He Ala His He Ala Gly His He

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 He Ala Lys He Ala Gly Lys

5 10

He Ala Lys He Ala Gly Lys He Ala Lys

15 20

He

(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

-102- ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 54 : He Ala Lys He Ala Gly Lys He Ala Lys

5 10

He Ala Gly Lye He Ala Lys He 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 He Ala Gly Arg He Ala Lys He Ala

5 10

Gly Arg He Ala Lys He Ala Gly Arg He

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 He Ala Gly Arg He Ala Arg He Ala 5 10

-103- Gly Arg He Ala Arg He Ala Gly Arg He

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 He Ala Lys Val Ala

5 10

Gly Lys He Ala Lys Val Ala Gly Lys He

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 He Ala Gly Lys Val Ala Lys He Ala

5 10

Gly Lys Val Ala Lys He Ala Gly Lyε Val

15 20

Ala

-104- (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 He Ala Gly Lys He Ala Lys He

5 10

Ala Gly Lys He Ala Lys He Ala Gly Lys

15 20

He

(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: Xaa is ornithine.

( i) SEQUENCE DESCRIPTION: SEQ ID NO:60: Xaa He Ala Gly Xaa He Ala Xaa lie Ala 5 10

Gly Xaa He Ala Xaa He Ala Gly Xaa He

15 20

Ala

(2) INFORMATION FOR SEQ ID NO:61:

-105- ( 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 He Ala Lys Phe Ala 5 10

Gly Lys He Ala Lys Phe Ala Gly Lys He

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 He Ala Gly Lys Phe Ala Lys He Ala 5 10

Gly Lys Phe Ala Lys He 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:

-106- (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 He Ala Lyε Xaa Ala

5 10

Gly Lys He Ala Lys Xaa Ala Gly Lys He

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: Xaa is norleucine.

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

Lys Xaa Ala Lys He Ala Gly Lys Xaa Ala

5 10

Lys He Ala Gly Lys Xaa Ala Lys He 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 He Ala Gly Lys He Ala Arg He Ala

5 10

Gly Lys He Ala Arg He Ala Gly Lys He

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.

( i) SEQUENCE DESCRIPTION: SEQ ID NO:66: Xaa He Ala Gly Xaa He Ala Xaa He Ala

5 10

Gly Xaa He Ala Xaa He Ala Gly Xaa He

15 20

Ala

(2)INFORMATION FOR SEQ ID NO:67:

(i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 21 amino acids

(B) TYPE: amino acid

-108- (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE: Xaa is p-aminophenylalanine

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

Xaa He Ala Gly Lys He Ala Xaa He Ala

5 10

Gly Lys He Ala Xaa He Ala Gly Lys He

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: Xaa is p-aminophenylalanine

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:

Lys He Ala Gly Xaa He Ala Lys He Ala

5 10

Gly Xaa He Ala Lys He Ala Gly Xaa He

15 20

Ala

(2) INFORMATION FOR SEQ ID NO:69: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 24 amino acids

(B) TYPE: amino acid

-109- (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:69: Lys He Ala Lys He Ala Gly Lyε He Ala

5 10

Lys He Ala Gly Lys He Ala Lys He Ala

15 20

Gly Lys He 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 He Ala Gly

5 10

Lys He 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

-110- (ix) FEATURE:

(D) OTHER INFORMATION: Xaa is ornithine.

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:71: Lys He Ala Gly Lys He Ala Lys He Ala Gly

5 10

Xaa He Ala Lys He Ala Gly Lys He 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 He Ala Gly Lys He Ala Lys He Ala

5 10

Gly Arg He Ala Lys He Ala Gly Lys He

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.

-111- ( i ) SEQUENCE DESCRIPTION : SEQ ID NO : 73 :

Lys He Ala Gly Lys He Ala Lys He Ala

5 10

Gly Xaa He Ala Lys He Ala Gly Lys He

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.

( i) SEQUENCE DESCRIPTION: SEQ ID NO:74: Lys He Ala Gly Lys He Ala Lys He Ala

5 10

Gly Xaa He Ala Lys He Ala Gly Lys He

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:

-112- (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: Xaa is ornithine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:76: Lys He Ala Gly Lys Phe Ala Lys He Ala

5 10

Gly Xaa Phe Ala Lys He 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

-113- (ix) FEATURE:

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

( i) SEQUENCE DESCRIPTION: SEQ ID NO:77: Lys He Ala Gly Lys Xaa Ala Lys He Ala

5 10

Gly Xaa Xaa Ala Lys He 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 He Ala

5 10

Gly Lys He 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

-114- ( Xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 79 Lys He Ala Ser Lys Ala Gly Lys He Ala

5 10

Gly Lys He 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 He Ala Ser Lys Ala Gly Lys Xaa Ala

5 10

Gly Lyε He 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.

■115- ( i) SEQUENCE DESCRIPTION: SEQ ID NO:81: Lys Leu Ala Ser Lyε Ala Gly Lyε Xaa Ala

5 10

Gly Lyε He 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 Lyε He 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.

-116- ( xi ) SEQUENCE DESCRIPTION : SEQ ID NO : 83 : Lys He Ala Gly Lys He Ala Lys He Ala

5 10

Gly Xaa He Ala Lys He Ala Gly Lys He

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 He Ala Gly Ala He Ala Lys He Ala

5 10

Gly Lys He Ala Lys He Ala Gly Lys He

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

-117- ( i ) SEQUENCE DESCRIPTION : SEQ ID NO : 85 : Lys He Ala Gly Lys He Ala Lyε He Ala

5 10

Gly Ala He Ala Lys He Ala Gly Lys He

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: Lyε He Ala Gly Lys He Ala Lys He Ala

5 10

Gly Lys He Ala Lys He Ala Gly Ala He

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

( i) SEQUENCE DESCRIPTION: SEQ ID NO:87: Lys Leu Ala Ser Lys Ala Ala Lys He Ala

5 10

Ala Lys He Ala Lys Val Ala Leu Lys Ala

-118- 15 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 He Ala Lys Lys He Ala Lys He Ala

5 10

Lys Lys He Ala Lys He Ala Lys Lys He

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:

-119- ( 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 He Ala Lys Phe Ala

5 10

Lys Lyε He Ala Lys Phe Ala Lyε Lys He

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 He Ala Gly Lys He Ala Lys He Ala

5 10

Gly Lys He Ala Lys He Ala Gly Lys He

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

-120- (ii) MOLECULE TYPE: peptide

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

Lys He Ala Gly Lys. He Ala Ala He Ala

5 10

Gly Lys He Ala Lyε He Ala Gly Lys He

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 He Ala Gly Lys He Ala Lys He Ala

5 10

Gly Lys He Ala Ala He Ala Gly Lys He

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

-121- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94: Gly Met Ala Ser Lys Ala Gly Lys He Ala

5 10

Gly Lys He 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 Lyε Lys Leu Lys Lys Leu Leu Lys

5 10

Leu Leu

(2) INFORMATION FOR SEQ ID NO:97:

-122- (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

-123- (ii) MOLECULE TYPE: peptide

(ix) SEQUENCE DESCRIPTION: SEQ ID NO:99: Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lyε Lyε 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 Lyε Lys Leu Leu Lys Lys Leu Lyε Lyε

5 10

Leu Leu Lys Lys Asn

15

-124- (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: amino 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 Lye Leu Leu Lys Lys Leu

15

(2) INFORMATION FOR SEQ ID NO:104: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 18 amino acids

(B) TYPE: amino acid

-125- (C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

( i) SEQUENCE DESCRIPTION: SEQ ID NO: 104: Leu Lys Leu Leu Lys Lys Leu Leu Lys Lyε

5 10

Pro Lyε Lyε 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 Gin Gly Pro Pro Gin Gly Gin Ser

15 20

Pro Gin

(2) INFORMATION FOR SEQ ID NO:106: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 20 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

-126- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106:

Leu Ala Ser Lys Ala Gly Ala He Ala Gly

5 10

Lys He Ala Lys Lyε 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 amino acids

(B) TYPE: amino 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 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

-127- (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

( i) SEQUENCE DESCRIPTION: SEQ ID NO:110: Lys Lys Leu Leu Lys Lys Leu Lys Lyε 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

-128- (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

-129- (vii ) FEATURE :

(A) NAME/KEY: melittin peptide

(x) PUBLICATION INFORMATION:

(A) AUTHORS: Haber ann, E.

Jentsch, J.

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

(C) JOURNAL: Hoppe-Seyler'ε Zeitschrift

Physiol. Chem.

(D) VOLUME: 348

(F) PAGES: 37-50

(G) DATE: 1987

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:114: Gly He Gly Ala Val Leu Lys Val Leu

5 Thr Thr Gly Leu Pro Ala Leu He Ser Trp 10 15

He Lys Arg Lys Arg Gin Gin 20 25

(2) INFORMATION FOR SEQ ID NO:115: (i) SEQUENCE CHARACTERISTICS

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

^■130- ( i) SEQUENCE DESCRIPTION: SEQ ID NO: 115: Gly He Gly Lys Phe Leu His Ser Ala Gly

5 10

Lys Phe Gly Lys Ala Phe Val Lys lie Met

15 20

Lys Ser

(2) INFORMATION FOR SEQ ID NO:116: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 26 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

•131- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 116:

Phe Ala Ser Phe Leu Gly Lys Ala Leu Lys

5 10

Ala Ala Leu Lys He Gly Ala Asn Leu Leu

15 20 Gly Gly Thr Pro Gin Gin

25

(2) INFORMATION FOR SEQ ID NO:117: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 27 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(Xi) SEQUENCE DESCRIPTION: SEQ ID NO:117: Gly Phe Ala Lys Phe Leu Gly Lys Ala Leu

5 10

Lys Ala Ala Leu Lys He Gly Ala Asn Leu

15 20

Leu Gly Gly Thr Pro Gin Gin

25

(2) INFORMATION FOR SEQ ID NO:118: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 amino acids

(B) TYPE: amino acids

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE:

(D) OTHER INFORMATION: amide-terminated

-132- (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 118: Gly He Gly Lys Phe Leu Lyε Lyε Ala Lyε

5 10

Lys Phe Gly Lys Ala Phe Val Lys He Met

15 20

Lys Lys

(2) INFORMATION FOR SEQ ID NO:119: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 35 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(ix) FEATURE: amide-terminated

-133- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:

Lys Trp Lys Leu Phe Lys Lys He Glu Lys Val Gly Arg Asn Gly 5 10 15

Arg Asn Gly He Val Lys Ala Gly Pro Ala He Ala Val Leu Ala 20 25 30

Leu Ala Leu Ala Leu 35

(2) INFORMATION FOR SEQ ID NO:120: (i) SEQUENCE CHARACTERISTICS:

(A) LENGTH: 22 amino acids

(B) TYPE: amino acid

(C) STRANDEDNESS:

(D) TOPOLOGY: linear

(ii) MOLECULE TYPE: peptide

(xi) FEATURE:

(D) OTHER INFORMATION: amide-terminated

(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 120: Gly He Gly Lys Phe Leu Lys Lys Ala Lys

5 10

Lys Phe Gly Lys Ala Phe Val Lys He Leu

15 20

Lys Lys

(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

-134- (Xi) SEQUENCE DESCRIPTION: SEQ ID NO: 121: Gly He Gly Lys Phe Leu Lys Lys Ala Lys

5 10

Lys Phe Ala Lys Ala Phe Val Lys He He

15 20

Asn Asn

■135-

Claims

WHAT IS CLAIMED IS:

1. A process for preventing or treating an adverse oral condition, comprising: adminiεtering to a host at least one biologically active amphiphilic peptide or protein, said peptide or protein being an ion channel-forming peptide or protein, said composition being administered in an amount effective to prevent or treat an adverse oral condition 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 X_. through X₃₇ wherein:

"31 is - l ₃₁-R₃₂-^R32^"R33^"R3l^"R32^"R32 ^C32 ^{i S " R}32^"R32^"R33^"R3l^"R32^_R32^"R31 ^C33 ^{i s " R}32^" 33~^R3l^"R32^"R32~^R3l^"R32 ^C34 ^{i8 " l R}33~^R31~^R32^"R32^"R31~^R32^"R32 ^ζ35 is -I R₃₁-R₃₂-^R32^"R31^"R32^"R32^"R33 and

^X36 ^{is " I R}32^"R32^'R3l^"R32^'R32^"R33^"R31 ^k37 is - t R₃₂-^R ₃ι-^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 X_4(J:

^R3l^"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 X_5Q:

■136- ^R4l^"R42^"R42^"R4l^"R42^"R42^"R4l^'R4l^"R42^"R4l^"R4l^"' ^{whβrein R} ₄₁ is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid;

(j) a peptide including the following basic structure X

52"

^R _A 42-_J~^R"4_A1_I~^R"_A42_'."^R"4_A2_'-~^R"_A4*1_!~^R _A4_I1"^R"_A42->"^R"4_A2-_J~^R"_A1_I~^R"4_A2_'-"R"42<_.-'' w^wh"e^Crⁱe^■=i^•*•n" R^R ₄₁ is a hydrophobic amino acid, and R._ is a basic hydrophilic or neutral hydrophilic amino acid;

(k) a peptide including the following basic structure x

54"

^"R4l^"R42^"R42~^R4l^"R4l^"R42~^R42^"R4l^"R42^"R42^"R41~^R4l^"

R₄-"^R 2~^R43"' wherein R₄- is a hydrophobic amino acid, R._ is a basic hydrophilic or neutral hydrophilic amino acid, and R._ is ι neutral hydrophilic amino acid;

(1) a peptide including the following basic structure X_ec:

56

^"R4l^"R42^"R4l^"R4l^'R42^"R42^"R4l^"R4l^"R42^"R42^"R44^"' ^wherein ₁ is a hydrophobic amino acid, R₄- 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 X_-:

^"R4l^"R4l^"R42^"R42^"R4l^"R42^"R42^"R4l^"R4l^"R42^"R42^"R4l^'R43' wherein R₄- is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R._ is a neutral hydrophilic amino acid;

(n) a peptide including the following basic structure X_g0:

^"R4l^"R4l^"R43^"R42^"R4l"^R4l^"R4l^"R4l^"R4l^"R4l^" 42^"R4l^"R4l^" ^R42~^R42~^R4l"^R4l"^R42"^R42~^R42"^R41' ^{wherβln R} i ^{is a} hydrophobic amino acid, ₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and ₄_ is a neutral hydrophilic amino acid;

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

⁽i^{) R}4i-^R42^"R42^"R4l^"R42^"R42^"R41'^" ⁽ii^{) R} ₄₁-^R ₁-^R42-^R42"^R4l^"R42^"R42^"R41^;

(iii^{) R} ₄₂-^R4i-^R4i-^R42"^R42^"R4l^"R42^"R42^"R41^; ⁽iv⁾ ₄₂-^R42- 41-^R41-^R42-^R42-^R4r^R42-^R42-^R41^{; and} ⁽v⁾ ₄₁-^R4₂-^R42-^R4r^R4r^R42-^R42-^R4r^R42^"R42-^R41' ^wherein

R₄₁ is a hydrophobic amino acid, and R_{42 i β a basic hydrophilic} amino acid or a neutral hydrophilic amino acid;

-137- (p) melittin;

(q) apidaecins;

(r) defensins;

(s) major basic protein of eosinophils;

(t) bacterial permeability-increaεing protein; and

(u) 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 X_. through X--, wherein: n^" ^X32 ^{is "lR}32~^R32^"R33^"R3l^"R32^"R32^"R31 33 ^{ia * R}32^"R33"^R3l^"R32^"R32^"R3l^"R32

^X34 ^{iB ■fR}33'^R3l^"R32^"R32^"R3l^"R32^"R32 ^X35 ^{iβ "tR}3l^"R32"^R32^"R3l^"R32^_R32^"R33

36 ^{is "ΪR}32^-R32^"R3l^"R32^"R32^'R33^"R31 and

37 ^iβ ~^fR32^-R3l^"R32~^R32^"R3333^"R"33l1^"R32 wherein R-. is a basic hydrophilic amino acid, R-- ^{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"

R„3,1-R"„32,,-R"3,2.,-R"3,3,-R"3,4„-R ^3„2"^R32"^R3l^"R32^R32^"R32^"R32^"R34^"R32^"R32' wherein R "3-_n1 is a basic hydrophilic amino acid, R 3,2, is a hydrophobic amino acid, R-₃ is a neutral hydrophilic, basic

•138- hydrophilic, or hydrophobic amino acid, and R_. is a basic hydrophilic or hydrophobic amino acid.

11. The process of Claim 10 wherein the petpide includes the following structure: s hereinabove described in Claim 14,

^{(iv) R}33^" 34~^R32^"R32^{; or} ^{(v) R}32-^R33^"R34-^R32-^R32^{; or} (vi) R₃₂-R₃₂-R₃3-R₃₄-R₃₂-R₃₂; or

(vii) R₃₁-R₃₂-R₃₂-R₃₃-R₃₄-R₃₂- ₃₂.

12. The process of Claim 10 wherein the peptide includes the following structure:

^X40^-Z40' ^{wherein X}4_Q ^{is aB} hereinabove described in Claim 10, and ∑₄₀ is:

⁽i^{) R}31-' ^or ⁽ii^{) R}3i-^R ₃₂-' ^or

(iii) R₃₁-R₃₂-R₃₂; or

(iv) R₃₁-R₃₂-R₃₂-R₃₃; or

^{(V) R}31^"R32-^R32-^R33-^R34^{; or} ⁽ i^{) R}31^"R32^"R32^-R33"^R34^-R32^{; or} (Vii) R₃₁-R₃₂-R₃₂-R₃₃-R₃₄-R₃₂-R₃₂.

13. The process of Claim 10 wherein the peptide includes the following structure:

^(Y40⁾a^"X40^"<Z40⁾b' ^{whβrβin Y}40 ^{and Z}40 ^{are as} P^reviously defined in Claims 11 and 12, a is 0 or 1, and b is 0 or 1.

14. The process of Claim 2 wherein said peptide includes the following basic structure Xe_n-

^R4l^"R42^"R42^"R4l^"R42^"R42^"R4l^"R4l^"R42^"R4l^"R41' wherein R-. is a hydrophobic amino acid, and R-₂ is a basic hydrophilic or neutral hydrophilic amino acid.

15. The process of Claim 2 wherein said peptide includes the following basic structure X_ς2*

^R42^"R4l^"R42^"R42^"R4l^"R4l^"R42^"R42^"R4l^"R42^"R42'

-139- wherein R... is a hydrophobic amino acid, and R₄_ is a basic hydrophilic or neutral hydrophilic amino acid.

16. The proceεs of Claim 2 wherein the peptide includes the following basic structure X₅₄:

^'R4l^"R42^"R42^"R4l^"R4l^"R42^"R42^"R4l^"R42^"R42^"R4l^"R4l^"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.

17. The process of Claim 2 wherein the peptide includes the following basic structure Xςg^:

~^R41~^R42~^R41~^R4l^"R42"^R42~^R4l"^R4l^"R42^"R42^"R44~' ^{whβrβin R} ₄₁ -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.

18. The process of Claim 2 wherein the peptide includes the following basic structure _ς -'

^"R4l^"R4l^"R42^"R42^"R4l^" 42^"R42^"R4l^"R4l^"R42^"R42^"R4l^"R43^"' ^wherβin R₄₁ is a hydrophobic amino acid, R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and R₄₃ is a neutral hydrophilic amino acid.

19. The process of Claim 2 wherein the peptide includes the following basic structure X_g0:

^" 4l^"R4l^"R43^"R42^"R4l^"R4l^"R4l^"R4l^"R4l^"R4l^"R42^"R4l^"R4l^"R42^"R42^"R4l^" -R₄--R₄₂-R₄₂-R₄₂-R₄₁-, wherein R₄₁ is a hydrophobic amino acid,

R₄₂ is a basic hydrophilic or neutral hydrophilic amino acid, and

R_Λ_ is a neutral hydrophilic amino acid.

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

⁽i^{) " R}4i"^R42~^R42^_R4l"^R42^"R42~^R41^{; '} ⁽ii^{) R}4l- 4l^_R42"^R42"^R41~^R42^"R42~^R41^; ⁽iii^{) R}42"^R4l"^R4l"^R42"^R42^"R4l^"R42^"R42^"R41^; ⁽iv⁾ ₄₂-^R42-^R41-^R41-^R42-^R42-^R41-^R42-^R42-^R41^{; and} ⁽v^{) R}4l-^R42~^R42"^R4l^"R4l^"R42^"R42^" 4l^"R42^"R42^" 41' wherein R.. is a hydrophobic amino acid, and R₄₂ is a basic hydrophilic amino acid or a neutral hydrophilic amino acid.

-140- 21. The process of Claim 2 wherein said peptide is melittin.

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

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

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

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

26. The proceβs of Claim 2 wherein said peptide or protein is perforin.

27. The process of Claim 1 wherein said composition further comprises an ion having pharmacological properties.

28. The process of Claim 1 wherein said composition further comprises chlorhexidine.

29. The proceβs of Claim 1 wherein said composition further comprises sanguinarine HCl.

30. The proceβs of Claim 27 wherein said ion having pharmacological properties is a fluoride ion.

31. The proceβs of Claim 1 wherein the peptide has the following structural formula:

-(Lys He Ala Lys Lys He Ala)_n-, wherein n is from 2 to 5.

32. The process of Claim 1 wherein the peptide has the following structural formula:

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

33. The process of Claim 1 wherein the peptide has the following structural formula:

-(Lys Phe Ala Lys Lys He Ala)_n ^«, wherein n is from 2 to 5.

•141-