AU2161592A - Composition and treatment with biologically active peptides having c-terminal substitutions - Google Patents

Composition and treatment with biologically active peptides having c-terminal substitutions

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Publication number
AU2161592A
AU2161592A AU21615/92A AU2161592A AU2161592A AU 2161592 A AU2161592 A AU 2161592A AU 21615/92 A AU21615/92 A AU 21615/92A AU 2161592 A AU2161592 A AU 2161592A AU 2161592 A AU2161592 A AU 2161592A
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peptide
amino acid
lys
ala
seq
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AU21615/92A
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U. Prasad Kari
W. Lee Maloy
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Magainin Pharmaceuticals Inc
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Magainin Pharmaceuticals Inc
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/463—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from amphibians
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

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  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Genetics & Genomics (AREA)
  • Molecular Biology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Communicable Diseases (AREA)
  • Oncology (AREA)
  • Virology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Description

COMPOSITION AND TREATMENT WITH BIOLOGICALLY
ACTIVE PEPTIDES HAVING C-TERMINAL SUBSTITUTIONS
This application is a continuation-in-part of application Serial No . 713 , 716 , filed June 12 , 1991 .
This invention relates to biologically active peptides and proteins , and more particularly to compositions rind uses
involving biological ly active peptides having C-terminal
substitutions .
In accordance with an aspect of the present invention, there is provided a composition comprising a C-termins] substituted peptide or protein of the formula :
wherein X is a biologically active amphiphilic peptide or protein. The peptide or protein is an ion channel-forming peptide or protein. T is selected from the group consisting of:
(a) OR, wherein R is a substituted or unsubstituted aliphatic, aromatic, or aralkyl group having from 1 to 10 carbon atoms. Preferably, R is an alkyl group. (The resulting
C-terminal substituted peptide is sometimes hereinafter referred to as a C-terminal ester.);
(b) NH-NH2 (The resulting C-terminal substituted peptide is sometimes referred to as a C-terminal hydrazide.); (c) NH-OH (The resulting C-terminal substituted peptide is sometimes hereinafter referred to as a C-terminal
hydroxylamine. ) ;
(d)
, wherein R' and R" are hydrogen or selected from the class consisting of group (i) and .group (ii), wherein; group (i) is a hydroxy-substituted aliphatic, aromatic, or aralkyl group having no more than 10 carbon atoms. Preferably, group (i) is a hydroxy-substituted alkyl group. Most preferably, group (i) is CH2CH2OH. Group (ii) is an amino-substituted aliphatic or aromatic, aralkyl, or alkylaromatic group.
Preferably the amino-substituted group has no more than 10 carbon atoms. Preferably, group (ii) is an amino-substituted alkyl group. Most preferably, group (ii) is CH2CH2NH2. The peptides terminated with group (d) are sometimes hereinafter referred to as substituted C-terminal amides.
As hereinabove stated, the peptide or protein is an ion channel-forming peptide or protein.
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.
Applicants have found that, when the C-terminal of the biologically active peptides is substituted with one of the groups hereinabove described, such peptides have increased biological activity as compared with peptides having
unsubstituted C-terminals.
The ion channel-forming peptides employed in the present
invention are generally water soluble to a concentration of at
least 20 mg/ml at neutral pH in water. In addition, the
structure of such peptide provides for flexibility of the peptide molecule. Such peptides are capable of forming an alpha-helical struct assume an amphiphilic structure. When the peptide encounters an oily surface or membrane, the peptide chain folds upon itself
into a rod-like structure.
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.
In general, the peptide or protein is administered topically at a concentration of from .05% to 10%. When administered
systemically, the peptide or protein is employed to provide
peptide or protein dosages of from lmg to 500mg per kilogram of host weight.
The compositions may be administered to a host; for example a human or non-human animal, in an amount effective to inhibit
growth of a target cell. Thus, for example, the compositions may be used as antimicrobial agents, anti-viral agents, antibiotics, anti-tumor agents, antiparasitic agents, antifungal agents,
spermicides, as well as exhibiting other bioactive functions.
The term "antimicrobial" as used herein means that the
peptides of the present invention inhibit, prevent, or destroy
the growth or proliferation of microbes such as bacteria, fungi, or the like.
The term "antibiotic" as used herein means that the peptides employed in the present invention produce effects adverse to the normal biological functions of the non-host cell, tissue, or
organism including death or destruction and prevention of the
growth or proliferation of the non-host cell, tissue, or organism when contacted with the peptides. The term "spermicidal" as used herein means that the peptides employed in the present invention, inhibit, prevent, or destroy the motility of sperm.
The term "antiviral" as used herein means that the peptides employed in the present invention inhibit, prevent, or destroy the growth or proliferation of viruses, or virally-infected cells.
The term anti-tumor as used herein means that the peptide inhibits the growth of or destroys tumors.
The term "antifungal" as used herein means that the peptide of the present invention may be used to inhibit the growth of or destroy fungi.
The term "antiparasitic" as used herein means that the peptides of the present invention may be used to inhibit the growth of or destroy parasites.
The peptides of the present invention have a broad range of potent antibiotic activity against a plurality of microorganisms including Gram-positive and Gram-negative bacteria, fungi, protozoa, and the like, as well as parasites. The peptides of the present invention allow a method for treating or controlling microbial infection caused by organisms which are sensitive to the peptides. Such treatment may comprise administering to a host organism or tissue susceptible to or affiliated with a microbial infection an antimicrobial amount of at least one of the peptides.
Because of the antibiotic, antimicrobial, and antiviral properties of the peptides, they may also be used as
preservatives or sterilants of materials susceptible to microbial or viral contamination.
The peptide and/or derivatives or analogues thereof may be administered in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or
physiological saline solution. Such pharmaceutical compositions may be used topically or systemically and may be in any suitable form such as a liquid, solid, semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule, or the like. The peptide compositions may also be used in combination with adjuvants, protein inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in
controlling infection caused by harmful microorganisms including protozoa and the like, as well as by parasites and viruses.
The peptide(s) of the present invention may be administered to a host; in particular an animal, in an effective antibiotic and/or anti-tumor and/or anti-viral and/or anti-microbial and/or anti-parasitic and/or an antispermicidal amount.
Depending on the use, a composition in accordance with the invention will contain an effective anti-microbial amount and/or an effective antispermicidal amount and/or an effective
anti-viral amount and/or an effective anti-tumor amount and/or an effective antibiotic amount and/or anti-parasitic amount of one or more of the hereinabove described peptides which have such activity.
The peptide of the present invention may also be employed in promoting or stimulating healing of a wound in a host.
The term "wound healing" as used herein includes various aspects of the would healing process.
These aspects include, but are not limited to, increased contraction of the wound, 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 of the present invention may also be employed so as to reverse the inhibition of wound healing caused by a depressed or compromised immune system.
The compositions of the present invention may also be used in the treatment of external burns and to treat and/or prevent skin and burn infections. In particular, the compositions may be used to treat skin and burn infections caused by organisms such as, but not limited to, P. aeruginosa and S. aureus.
The peptides of the present invention may be used in the treatment of external burns and to treat and/or prevent skin and burn infections. In particular, the peptides may be used to treat skin and burn infections cause by organisms such as, but not limited to, P. aeruginosa and S. aureus.
The peptides are also useful in the prevention or treatment of eye infections. Such infections may be caused by bacteria such as, but not limited to, P. aeruginosa, S. aureus, and N. gonorrhoeae, by fungi such as but not limited to C. albicans and A. fumigatus, by parasites such as but not limited to A.
castellani, or by viruses.
The peptides may also be effective in killing cysts, spores, or trophozoites of infection - causing organisms. Such organisms include, but are not limited to Acanthamoeba which forms
trophozoites or cysts, C. albicans, which forms spores, and A. fumigatus, which forms spores as well.
The peptides may also be administered to plants in order to prevent, inhibit, or destroy the growth of microbes, bacteria, fungi, viruses, cysts, spores, or parasites in plants.
In accordance with one embodiment, each of the amino acid residues of the peptide or protein is a D-amino acid residue or glycine. Although the scope of this particular embodiment is not to be limited to any theoretical reasoning, it is believed that the peptide or protein, when consisting entirely of D-amino acid or glycine residues, may have increased resistance to proteolytic enzymes while retaining their biological activity. Such peptides or proteins thus may be administered orally. Also, in accordance with another embodiment, all of the amino acid residues are
D-amino acid or glycine residues, or L-amino acid or glycine residues.
In accordance with a preferred embodiment, the peptide is a basic (positively charged) polypeptide having at least sixteen amino acids wherein the polypeptide includes at least eight hydrophobic amino acids and at least eight hydrophilic amino acids. Still more particularly, the hydrophobic amino acids are in groups of two adjacent amino acids, and each group of two hydrophobic amino acids is spaced from another group of two hydrophobic amino acids by at least one amino acid other than a hydrophobic amino acid (preferably at least., two amino acids) and generally by no greater than four amino acids, and the amino acids between pairs of hydrophobic amino acids may or may not be hydrophilic.
The hydrophilic amino acids are generally also in groups of two adjacent amino acids in which at least one of the two amino acids is a basic hydrophilic amino acid, with such groups of two hydrophilic amino acids being spaced from each other by at least one amino acid other than a hydrophilic amino acid (preferably at least two amino acids) and generally no greater than four amino acids, and the amino acids between pairs of hydrophilic amino acids may or may not be hydrophobic.
In accordance with a particularly preferred embodiment, the polypeptide comprises a chain of at least four groups of amino acids, with each group consisting of four amino acids. Two of the four amino acids in each group are hydrophobic amino acids, and two of the four amino acids in each group are hydrophilic, with at least one of the hydrophilic amino acids in each group being a basic hydrophilic amino acid and the other being a basic or neutral hydrophilic amino acid.
The hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, 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, Gln, Ser, and Thr and homoserine (Hse). The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2, 4 - diaminobutyric acid (Dbu), and p-aminophenylalanine. Each of the groups of four amino acids may be of the sequence ABCD, BCDA, CDAB, or DABC, wherein A and B are each hydrophobic amino acids and may be the same or different, one of C or D is a basic hydrophilic amino acid, and the other of C or D is a basic or neutral hydrophilic amino acid and may be the same or different. In 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.
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 ςrroups 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 provide 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 havin at least 20 amino acids but no greater than 50 amino acids.
In one embodiment, each of the at least four groups of amino acids which are in the peptide chain is of the sequence A-B-C-D, B-C-D-A, C-D-A-B or D-A-B-C wherein A and B are hydrophobic amino acids, one of C or D is a basic hydrophilic amino acid, and the other of C or D is basic or neutral hydrophilic amino acid. The resulting polypeptide chain, therefore, may have one of the following sequences:
(X1)a(A-B-C-D)n(Y1)b
(X2)a(B-C-D-A)n(Y2)b
(X3)a(C-D-A-B)n(Y3)b
(X4)a(D-A-B-C)n(Y4)b
wherein X1 is D; C-D- or B-C-D-, Y1 is -A or -A-B or -A-B-CX2 is A-, D-A- or C-D-A-Y2 is -B, -B-C or B-C-D
X3 is B-, A-B-, D-A-B-Y3 is -C, -C-D, -C-D-A
X4 is C-, B-C-, A-B-C-
Y4 is -D, -D-A, -D-A-B
a is 0 or 1; b is 0 or 1
and n is at least 4.
It is to be understood that the peptide chain may include amino acids between the hereinabove noted groups of four amino acids provided that the spacing between such groups and the charge on the amino acids does not change the characteristics of the peptide chain which provide amphiphilicity and a positive charge and do not adversely affect the folding characteristics of the chain to that which is significantly different from one in which the hereinabove noted group of four amino acids are not spaced from each other.
As representative examples of 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-Ser-Lys-Ala-Phe-Ser-Lys (SEQ ID NO:1)
II Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser- Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe- Ser-Lys. (SEQ ID NO:2)
III Phe-Ser-Lys-Ala-Phe-Ser- Lys-Ala-Phe-Ser-Lys-Ala- (SEQ ID NO: 3)
Phe-Ser-Lys-Ala- IV Ser-Lys-Ala-Phe-Ser-Lys-Ala- Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala- (SEQ ID NO : 4)
Phe-Ser-Lys-Ala-Phe-
V Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser- Lys-Ala-Phe-Ser (SEQ ID NO: 5)
The peptide, may have amino acids extending from either end of the chain. For example, the chains may have a Ser-Lys sequence before the "Ala" end, and/or an Ala-Phe sequence after the "Lys" end. Other amino acid sequences may also be attached to the "Ala" and/or the "lys" end.
Similarly, in any polypeptide chain having at least four groups of amino acids of the sequence as described above, the chain may have, for example, a C-D sequence before the first A-B-C-D group. Also other amino acid sequences may be attached to the "A" and/or the "D" end of one of these polypeptide chains. Also there may be amino acids in the chain which space one or more groups of the hereinabove noted four amino acids from each other.
The peptides with the substituted C-terminals may be
synthesized by either solid phase peptide synthesis or solution methods of peptide synthesis. When solid phase peptide synthesis is employed, the peptide, with appropriate side chain protection, is synthesized by established methods on a suitable resin. The protected peptide resin is suspended in methanol (25 ml/g of resin) and stirred with a large excess of an appropriate amino component for several days in order to produce a C-terminal substituted hydrazide, hydroxylamine, or amide having one of the structures hereinabove described. When a diamino compound is used, one of the amino groups is suitably protected. The peptide plus resin is filtered, washed with methanol, and dried. The resin and peptide mixture is subjected to HE treatment and the deprotected peptide amide, hydroxylamine, or hydrazide is
extracted with dilute acetic acid and lyophilized. The C-terminal esters can be obtained by transesterification of the peptide with an appropriate alcohol as solvent in the presence of a tertiary base such as triethylamine. The work up and the isolation of the peptide ester is similar to the
procedure for isolating the other C-terminal substituted
peptides.
When the synthesis is carried out by standard solution methods of peptide synthesis, the C-terminal substituted ester peptide may be made by beginning the solution synthesis with an appropriate amino acid ester. If other modified C-terminal peptides are desired, the protected peptide C-terminal ester may be reacted with hydroxylamine or hydrazine to produce an
appropriate peptide C-terminal hydroxylamine or peptide
C-terminal hydrazide, respectively.
If a peptide C-terminal substituted amide is desired, the C-terminal ester is hydrolyzed by standard techniques, and the protected peptide acid is reacted with the desired amino
component (suitably protected) by standard coupling procedures. The protected peptide derivative is then deprotected and
purified.
It is also possible to produce the peptides in unsubstituted form by genetic engineering techniques. The codons encoding the amino acids of the peptides 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 transfect such an expression vehicle into a cell which will express the peptides. Upon expression of such peptide, the peptide may be substituted at the C-terminal in accordance with the present invention by techniques such as those hereinabove described.
In accordance with another preferred embodiment, the peptide may be a magainin peptide.
A magainin peptide is either a magainin such as magainin I, II or III or an analogue or derivative thereof. The magainin peptides preferably include the following basic peptide structure X12:
-- R11-R11-R12-R13-R11-R14-R12-R11-
R14-R12-R11-R11-R11-R14a-(R15)n-R14a-R14 -- wherein R11 is a hydrophobic amino acid, R11 is a basic hydrophilic amino acid; R13 is a hydrophobic, neutral
hydrophilic, or basic hydrophilic amino acid; R14 and R14a are hydrophobic or basic hydrophilic amino acids; R15 is glutamic acid or aspartic acid, or a hydrophobic or a basic hydrophilic amino acid, and n is 0 or 1. In a preferred embodiment, R13 is a hydrophobic or neutral hydrophilic amino acid, R14a 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 X12 is the hereinabove described basic peptide
structure and Y12 is
(i) R12
(ii) R14a-R12
(iii) R11-R14a-R12
(iv) R14-R11-R14a-R12
where R11, R12, R14 ancl R14a are as Previousiy defined.
A magainin peptide may also have the following structure:
-X12-Z12- wherein X12 is as previously defined and Z12 is:
(i) R16 where R16 is a basic hydrophilic amino acid or asparagine or glutamine.
(ii) R16-R17 where R17 is a neutral hydrophilic amino acid, a hydrophobic amino acid, or a basic hydrophilic amino acid.
Preferably, R17 is a neutral hydrophilic amino acid.
A magainin peptide may also have the following structure:
(Y12)a-X12-(Z12)b where X12, Y12 and Z12 are as Previously defined and a is 0 or 1 and b is 0 or 1.
The magainin peptides may also include the following basic peptide structure x13 :
--R14-R11-R14a-R12-R11-R11-R12-R13- R11-R14-R12-R11-R11-R12-, wherein R11,R12,R13, R14, and R14a are amino acids as hereinabove described.
The magainin peptide may also include the following
structure X13-Z13; wherein X13 is the hereinabove described basic peptide structure and Z13 is
(R11)n-(R11)n-(R11)n-(R14a)n-(R15)n-(R14a)n-(R14)n-(R16)n-(R17)n wherein R11, R14, R14a, R15, R16, and R17 are as hereinabove described, and n is 0 or 1, and each n may be the same or
different.
The magainin peptides generally include at least fourteen amino acids and may include up to forty amino acids. A magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove described basic peptide structures of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
As representative examples of such magainin peptides, there may be mentioned peptides having the following primary sequences as given in the accompanying sequence listing as well as
appropriate analogues and derivatives thereof:
(a) (SEQ ID N0:6)
(Magainin I)
(b) (SEQ ID N0:7)
(Magainin II)
(c) (SEQ ID N0:8)
(Magainin III)
The following are examples of peptide derivatives or analogs of the basic structure:
(d) (SEQ ID N0:9)
(e) (SEQ ID NO: 10) ( f ) ( SEQ ID NO : 11 )
Magainin peptides are described in Proc. Natl. Acad Sci. Vol. 84 pp. 5449-53 (Aug. 87). The term "magainin peptides" as used herein refers to the basic magainin structure as well as derivatives and analogs thereof, including but not limited to the representative derivatives or analogs.
In accordance with a further embodiment, the peptide may be a PGLa peptide or an XPF peptide.
A PGLa peptide is either PGLa or an analogue or derivative thereof. The PGLa peptides preferably include the following basic peptide structure X14:
- R11-R17-R12-R11-R14-R14-R11- R11-R14-R12-R11-R11-R12-R11- R11-R11-R12- where R11, R12, R14, and R17 are as Previously defined.
The PGLa peptides generally include at least seventeen amino acids and may include as many as forty amino acids. Accordingly, the hereinabove described basic peptide structure for a PGLa peptide may include additional amino acids at the amino end or at the carboxyl end or at both the amino and carboxyl end.
Thus, for example, a PGLa peptide may have the following structure:
-Y14-X14- where X14, is as previously defined and
Y14 is
(i) R11;
(ii) R14-R11
where R11 and R14 are as previously defined.
For example, a PGLa peptide may also have the following structure:
-X14-Z14- where X14 is as previously defined; and Z14 is :
(i ) R11; or
(ii ) R11-R11 where R11 is as previously defined.
A PGLa peptide may also have the following structure:
(Y14)a-X14-(Z14)b
where X14; Y14 and Z14 are as previously defined, a is 0 or 1 and b is 0 or 1.
An XPF peptide is either XPF or an analogue or derivative thereof. The XPF peptides preferably include the following basic peptide structure X16:
—R11-R17-R12-R11-R14-R18-R17-
R11-R14-R12-R11-R11-R12-
R11- R11- R11-R12-(R15)n-R11 -' wherein
R11, R12, R14, R15 and R17 are as Previously defined and Rιa is glutamine or asparagine or a basic hydrophilic, or hydrophobic amino acid and, n is 0 or 1.
The XPF peptides generally include at least nineteen amino acids and may include up to forty amino acids. Accordingly, the hereinabove described basic peptide structure of XPF may include additional amino acids at the amino end, or at the carboxyl end or at both the amino and carboxyl ends.
Thus, for example, an XPF peptide may include the following structure:
-Y16-X16- where X16 is as previously defined and Y16 is
(i) R11 or
(ii) R14-R11
where R11 and R14 are as previously defined.
An XPF peptide may include the following structure:
-X16-Z16- where X16 is as previously defined and Z16 is
(i) R11; or
(ii) R11-R18; or
(iii) R11-R18-Proline; or
(iv) R11-R18-Proline-R12 An XPF peptide may also have the following structure:
(γ16)a-X16(Z16)b
where X16, Y16 and Z16 are as previously defined: a is 0 or 1 and b is 0 or 1.
Preferred are XPF or PGLa peptides, which are characterized by the following primary amino acid sequences as given in the accompanying sequence listing:
PGLa : (SEQ ID NO: 12)
XPF : (SEQ ID NO: 13)
A review of XPF and PGLa can be found in Hoffman et al, EMBO J. 2:711-714, 1983; Andreu et al, J. Biochem. 149:531-535, 1985; Gibson et al J. Biol. Chem. 261:5341-5349, 1986; and Giovannini et al, Biochem J. 243:113-120, 1987.
In accordance with yet another embodiment, the peptide may be a CPF peptide or appropriate analogue or 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 X20 :
-R21-R21-R22-R22-R21-R21-R23-R21-
-R21-R21-R23-R21-R21-R24-R25-R21- wherein R21 is a hydrophobic amino acid;
R77 is a hydrophobic amino acid or a basic hydrophilic amino acid;
R23 is a basic hydrophilic amino acid;
R24 is a hydrophobic or neutral hydrophilic amino acid; and
R25 is a basic or neutral hydrophilic amino acid.
The hereinabove basic structure is hereinafter symbolically indicated as X20.
The hydrophobic amino acids are Ala, Cys, Phe, Gly, lie, Leu, Met, Val, Trp, Tyr, norleucine (Nle), norvaiine (Nval), and cyclohexylalanine (Cha). The neutral hydrophilic amino acids are Asn, Gln, Ser, and Thr.
The basic hydrophilic amino acids are Lys, Arg, His, Orn, homoarginine (Har), 2, 4-diaminobutyric acid (Dbu), and
p-aminophenylalanine.
The CPF peptide may include only the hereinabove noted amino acids or may include additional amino acids at the amino and/or carboxyl end or both the amino and carboxyl end. In general, the peptide does not include more than 40 amino acids.
The CPF peptides including the above basic structure
preferably have from 1 to 4 additional amino acids at the amino end.
Accordingly, such preferred peptides may be represented by the structural formula:
Y20 - X20 - wherein X20 is the hereinabove described basic peptide structure and Y20 is
(i) R25-, or
(ii) R22-R25-; or
(iii) R21-R22-R25; or
(iv) R22-R21-R22-R25; Preferably
Glycine - R21-R22-R25.
wherein R21, R22 and R25 are as Previously defined.
The carboxyl end of the basic peptide structure may also have additional amino acids which may range from 1 to 13
additional amino acids.
In a preferred embodiment, the basic structure may have from 1 to 7 additional amino acids at the carboxyl end, which may be represented as follows:
-X20 - Z20 wherein
X is the hereinabove defined basic peptide structure and Z20 is
(i) R21- , or
(ii) R21-R21- ; or (iii ) R21- R21-R24; or
(iv) R21-R21-R24-R24; or
(v) R21-R21-R24-R24-R26; or
(vi ) R21-R21-R24-R24-R26-Gln; or
(vii) R21-R21-R24-R24-R26-Gln-Gln, wherein R21 and R24 are as previously defined, and R26 is proline or a hydrophobic amino acid.
Preferred peptides may be represented by the following structural formula
(Y20)a - X20 - (Z20)b wherein X20, Y20 and Z20 are as Previously defined and a is 0 or 1 and b is 0 or 1.
Representative examples of CPF peptides which may be employed, some of which have been described in the literature, include the following sequences as given in the accompanying sequence listing:
(SEQ ID NO: 14)
(SEQ ID NO: 15)
(SEQ ID NO: 16)
(SEQ ID NO: 17)
(SEQ ID NO: 18)
(SEQ ID NO:19)
( SEQ ID NO: 20 )
(SEQ ID N0: 21)
( SEQ ID NO: 22 )
(SEQ ID N0: 23 )
( SEQ ID NO: 24)
( SEQ ID NO: 25 )
(SEQ ID NO: 26)
The above is expressed as single letter code for amino acids. A review of the CPF peptides can be found in Richter, K., Egger, R., and Kreil (1986) J. Biol. Chem 261, 3676-3680; Wakabayashi, T., Kato, H., and Tachibaba, S. (1985) Nucleic Acids Research 13, 1817-1828; Gibson, B.W., Poulter, L., Williams, D.H., and Maggio, J.E. (1986) J. Biol. Chem 261, 5341-5349.
In accordance with yet another embodiment, the peptide may include one of the following basic structures X31 through X37 wherein
X 31 is -[R31-R32-R32-R33-R31-R32-R32]-n;
X32 is -[R32-R32-R33-R3l-R32-R32-R31]-n;
X33 is -[R32-R33-R3l-R32-R32-R31-R32]-n;
X 34 is -[R33-R31-R32-R32-R31-R32-R32]-n;
X35 is -[R31-R32-R32-R31-R32-R32-R33]-n;
X 36 is -[R32-R32-R31-R32-R32-R33-R31]-n; and
X37 is -[R32-R31-R32-R32-R33-R31-R32]-n;
wherein R 31 is a basic hydrophilic amino acid, R 32 is a
hydrophobic amino acid, R33 is a neutral hydrophilic or
hydrophobic amino acid, and n is from 2 to 5.
The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2, 4-diaminobutyric acid (Dbu), and p-aminophenylalanine.
The hydrophobic amino acids may be selected from the class consisting of Ala, Cys, Phe, Gly, lie, Leu, Met, Val, Trp and Tyr, norleucine (Nle), norvaiine (Nva), and cyclohexylalanine (Cha).
The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser and Thr.
In accordance with one embodiment, when the peptide includes the structure X31, the peptide may include the following
structure:
Y31-X31, wherein X31 is as hereinabove described, and Y31 is:
(i) R 32;
(ii) R32-R32; (iii ) R31-R32-R32 ;
( iv) R33-R31-R32-R32 ;
(v) R32-R33-R31-R32-R32 ; or
(vi) R32-R32-R33-R31-R32-R32, wherein R31, R32, and R33 are as hereinabove described
In accordance with another embodiment, when the peptide includes the structure X31, the peptide may include the following structure:
X31-Z31, wnerein X31 is as hereinabove described, and Z31 is:
(i) R31;
(ii) R31-R32;
(iii) R31-R32-R32;
(iv) R31-R32-R32-R33;
(v) R31-R32-R32-R33-R31; or
(vi) R31-R32-R32-R33-R31-R32.
In accordance with yet another embodiment, the peptide may include the following structure:
(Y31) -X31-(Z31)b, wherein Y31 and Z31 are as previously defined, a is 0 or 1, and b is 0 or 1.
When the peptide includes the structure X32, tne peptide may include the following structure:
Y32 - X32, wnerein X32 is as hereinabove described, and Y32 is:
(i) R31;
( ii ) R32-R31 ;
( iii) R32-R32-R31 ;
( iv) R31-R32-R32-R31;
(v) R33-R3 1-R32-R32-R31 ; or
(vi ) R32-R33-R31-R32-R32-R31 .
In another embodiment, when the peptide includes the
structure X32, the peptide may include the following structure:
X32 - Z32, wnerein X32 is as hereinabove described, and Z32 is: ( i ) R32 ;
( ii ) R32-R32 ;
(iii) R32-R32-R33;
(iv) R32-R32-R33-R31;
(v) R32-R32-R33-R31-R32; or
(vi) R32-R32-R33-R31-R32-R32.
In accordance with yet another embodiment, the peptide may include the following structure:
(Y32)a - X32 - (Z32)b, wherein Y32 and Z32 are as previously defined, a is 0 or 1, and b is 0 or 1.
In accordance with another embodiment, when the peptide includes the structure X33, the peptide may include the following structure:
Y33 - X33 wherein X33 is as hereinabove described, and Y33 is:
(i) R32;
(ii) R31-R32;
(iii) R32-R31-R32;
(iv) R32-R32-R31-R32;
(v) R31-R32-R32-R31-R32; or
(vi) R33-R31-R32-R32-R31-R32, wherein R31, R32, and R33 are as hereinabove described.
In accordance with another embodiment, when the peptide includes the structure X33, the peptide may include the following structure:
X33 - Z33 wherein X33 is as hereinabove described, and Z33 is:
(i) R32;
(ii) R32-R33;
(iii) R32-R33-R31;
(iv) R32_R33-R31-R32;
(v) R32-R33-R31-R32-R32; or
(vi) R32-R33-R31-R32-R32-R31- In accordance with yet another embodiment, the peptide may include the following structure:
(Y33)a - X33 - (Z33)b, wherein Y33 and Z33 are as previously defined, a is 0 or 1, and b is 0 or 1.
In accordance with yet another embodiment, when the peptide includes the structure X34, the peptide may include the following structure:
Y34 - X34, wherein X34 is as hereinabove described, and Y34 is:
(i) R32;
(ii) R32-R32;
(iii) R31-R32-R32;
(iv) R3 Y2-R31-R32-R32;
(v) R32-R32-R31-R32-R32; or
(vi) R31-R32-R32-R31-R32-R32, wherein R31, R32 and R33 are as hereinabove described.
In accordance with another embodiment, when the peptide includes the structure X34. the peptide may include the following structure:
X34-Z34' wherein X34 is as hereinabove described, and Z34 is:
(i) R33;
(ii) R33-R31;
(iii) R33-R31-R32;
(iv) R33-R3l-R32-R32;
(v) R33-R31-R32-R32-R31; or
(vi) R33-R31-R32-R32-R31-R32.
In accordance with yet another embodiment, the peptide may include the following structure:
(Y34)a- X34- (Z34)b, wherein X34 and Z34 are as previously defined, a is 0 or 1, and b is 0 or 1.
In accordance with a further embodiment, when the peptide includes the structure X35, the peptide may include the following structure: Y35-X35, wherein X35 is as hereinabove described, and Y35 is:
(i) R33;
(ii) R32-R33;
(iii) R32-R32-R33;
(iv) R31-R32-R32-R33;
(v) R32-R31-R32-R32-R33; or
(vi) R32-R32-R31-R32-R32-R33, wherein R31, R32, and R33 are as hereinabove described.
In accordance with another embodiment, when the peptide includes the structure X35, the peptide may include the following structure:
X35 - Z35 wherein X35 is as hereinabove described, and Z35
IS:
(i) R31;
(ii) R31-R32;
(iii) R31-R32-R32;
(iv) R31-R32-R32-R31;
(v) R31-R32-R32-R31-R32; or
(vi) R31-R32-R32-R31-R32-R32.
In accordance with yet another embodiment, the peptide may include the following structure:
(Y35) - X35 (z35)b, wherein X35 and Z35 are as previously defined, a is 0 or 1, and b is 0 or 1.
In accordance with a further embodiment, when the peptide includes the structure X36, the peptide may include the following structure :
Y36 - X36 wherein X36 is as hereinabove described, and Y36 i s :
( i ) R31 ;
(ii) R33-R31 ;
(iii) R32-R33-R31 ;
( iv) R32-R32-R33-R31 ;
(v) R31-R32-R32 -R33 -R31 ; or (vi) R32-R31-R32-R32-R33-R31, wherein R31, R32, and R33 are as hereinabove described.
In accordance with another embodiment, when the peptide includes the structure X36, the peptide may include the following structure:
X36-Z36, wherein X36 is as hereinabove described, and Z36 is:
(i) R32;
(ii) R32-R32;
(iii) R32-R32-R31;
(iv) R32-R32-R31-R32;
(v) R32-R32-R31-R32-R32; or
(vi) R32-R32-R31-R32-R32-R33.
In accordance with yet another embodiment, the peptide may include the following structure:
(Y36)a- X36 (Z36)b, wherein Y36 and Z36 are as previously defined, a is 0 or 1, and b is 0 or 1.
In accordance with one embodiment, when the peptide includes the structure X37, the peptide may includes the structure
Y37-X37, wherein X37 is as hereinabove described, and Y37 is:
(i) R32;
(ii) R31-R32;
(iii) R33-R31-R32;
(iv) R32-R33-R31-R32;
(v) R32-R32-R33-R31-R32; or
(vi) R31-R32-R32-R33-R31-R32, wherein R31, R32, and R33 are as hereinabove described.
In accordance with a further embodiment, when the peptide includes the structure X37, the peptide may include the following structure:
X37 - Z37 wherein X37 is as hereinabove described, and Z37 is:
(i) R32;
(ii) R32-R31; ( iii ) R32-R31-R32 ;
( iv) R32-R31-R32-R32 ;
(v) R32-R3 1-R32-R32-R33 ; or
(vi ) R32-R31-R32-R32-R33-R31 .
In accordance with yet another embodiment, the peptide may include the following structure:
(Y37)a- X37 (Z37)b, wherein Y37 and Z37 are as previously defined, a is 0 or 1, and b is 0 or 1.
In a preferred embodiment, n is 3, and most preferably the peptide has one of the following structures:
(Lys Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO:27).
(Lys Ile Ala Lys Ile Ala Gly)3 (SEQ ID NO: 28).
(Lys Ile Ala Gly Lys Ile Gly)3 (SEQ ID NO: 29).
(Lys Leu Ala Gly Lys Leu Ala)3 (SEQ ID NO: 30).
(Lys Phe Ala Gly Lys Phe Ala)3 (SEQ ID NO: 31).
( Lys Ala Leu Ser Lys Ala Leu) 3 ( SEQ ID NO: 32 )
(Lys Leu Leu Lys Ala Leu Gly)3 (SEQ ID NO: 33)
(Lys Ala Ile Gly Lys Ala Ile)3 (SEQ ID NO: 34)
(Gly Ile Ala Lys Ile Ala Lys)3 (SEQ ID NO: 35)
(Lys Ile Ala Lys Ile Phe Gly)3 (SEQ ID NO: 36)
(Gly Ile Ala Arg Ile Ala Lys)3 (SEQ ID NO: 37)
(Lys Phe Ala Arg Ile Ala Gly)3 (SEQ ID NO: 38)
(Gly Phe Ala Lys Ile Ala Lys)3 (SEQ ID NO: 39)
(Lys Ile Ala Gly Orn Ile Ala)3 (SEQ ID NO: 40)
(Lys Ile Ala Arg Ile Ala Gly)3 (SEQ ID NO: 41)
(Orn Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO: 42)
(Gly Ile Ala Arg Ile Phe Lys)3 (SEQ ID NO: 43)
(Lys Nle Ala Gly Lys Nle Ala)3 (SEQ ID NO: 44)
(Lys Nle Ala Gly Lys Ile Ala)3 (SEQ ID NO: 45)
(Lys Ile Ala Gly Lys Nle Ala)3 (SEQ ID NO: 46)
(Lys Nva Ala Gly Lys Nva Ala)3 (SEQ ID NO: 47)
(Lys Nva Ala Gly Lys Ile Ala)3 (SEQ ID NO: 48)
(Lys Leu Leu Ser Lys Leu Cly)3 (SEQ ID NO: 49)
(Lys Leu Leu Ser Lys Phe Gly)3 (SEQ ID NO: 50) (Lys Ile Ala Gly Lys Nva Ala)3 (SEQ ID NO: 51)
(His Ile Ala Gly His Ile Ala)3 (SEQ ID NO: 52)
(Ala Gly Lys Ile Ala Lys Ile)3 (SEQ ID NO: 53)
(Ile Ala Lys Ile Ala Gly Lys)3 (SEQ ID NO: 54)
(Lys Ile Ala Gly Arg Ile Ala)3 (SEQ ID NO: 55)
(Arg Ile Ala Gly Arg Ile Ala)3 (SEQ ID NO: 56)
(Lys Val Ala Gly Lys Ile Ala)3 (SEQ ID NO: 57)
(Lys Ile Ala Gly Lys Val Ala)3 (SEQ ID NO: 58)
(Ala Lys Ile Ala Gly Lys Ile)3 (SEQ ID NO: 59)
(Orn Ile Ala Gly Orn Ile Ala)3 (SEQ ID NO: 60)
(Lys Phe Ala Gly Lys Ile Ala)3 (SEQ ID NO: 61)
(Lys Ile Ala Gly Lys Phe Ala)3 (SEQ ID NO: 62)
(Lys Cha Ala Gly Lys Ile Ala)3 (SEQ ID NO: 63)
(Lys Nle Ala Lys Ile Ala Gly)3 (SEQ ID NO: 64)
(Arg Ile Ala Gly Lys Ile Ala)3 (SEQ ID N0: 65)
(Har Ile Ala Gly Har Ile Ala)3 (SEQ ID NO: 66)
(Xaa Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO: 67)
(Lys Ile Ala Gly Xaa Ile Ala)3 (SEQ ID NO: 68)
(Lys Ile Ala (Lys Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO:69)
In (SEQ ID NO: 67) and (SEQ ID NO: 68), Xaa is
p-aminophenylalanine.
In accordance with another embodiment, the biologically active amphiphilic peptide which includes the following basic structure X40:
R31-R32-R32-R33-R34-R32-R32-R3l-R32-R32-R32-R34-R32-R32, wherein R31, R32, and R33 are as hereinabove described, and
R34 is a basic hydrophilic or hydrophobic amino acid.
In accordance with one embodiment, the peptide may include the following structure:
Y40-X40, wherein X40 is as hereinabove described, and Y40 is:
(i) R32;
(ii) R32-R32;
(iii) R34-R32-R32; (iv) R33-R34-R32-R32;
(v) R32-R33-R34-R32-R32;
(v) R32-R32-R33-R34-R32-R32, or
(vii) R31-R32-R32-R33-R34-R32-R32,wherein R31, R32, R33 and R 34 are as hereinabove described.
In accordance with another embodiment, the peptide may include the following structure:
X40-Z40, wherein X40 is as hereinabove described and Z40 is: (i) R31;
(ii) R31-R32;
(iii) R31-R32-R32;
(iv) R31-R32-R32-R33;
(v) R31-R32-R32-R33-R34;
(vi) R31-R32-R32-R33-R34-R32; or
(vii) R31-R32-R32-R33-R34-R32-R32, wherein R31, R32, R33, and R34 are as hereinabove described.
In accordance with yet another embodiment the peptide may include the following structure:
(Y40)a-X40-(Z40)b, wherein Y40 and Z40 are as previously defined, a is 0 or 1, and b is 0 or 1. In a preferred
embodiment, the peptide has the following structural formula as given in the accompanying sequence listing:
(SEQ ID NO: 70)
In another preferred embodiment, the peptide has the
following structural formula as given in the accompanying
sequence listing:
(SEQ ID NO: 71)
In accordance with a further embodiment, the peptide has one of the following structural formulae as given in the accompanying sequence listing:
(SEQ ID NO: 72)
(SEQ ID NO: 73)
(SEQ ID NO: 74)
(SEQ ID NO: 75) (SEQ ID NO: 76)
(SEQ ID NO: 77)
(SEQ ID NO: 78)
(SEQ ID NO: 79 )
(SEQ ID NO: 80)
(SEQ ID NO: 81)
( SEQ ID NO: 82 )
(SEQ ID NO: 83)
(SEQ ID NO: 84)
(SEQ ID NO: 85)
(SEQ ID NO: 86)
(SEQ ID NO: 87)
In accordance with another embodiment, the peptide may include the following structural formula:
-(Lys Ile Ala Lys Lys Ile Ala)-n, wherein n is from 2 to 5. Preferably, n is 3, and the peptide has the following structural formula:
(Lys Ile Ala Lys Lys Ile 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)-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 Phe Ala)3
(SEQ ID NO:89)
In accordance with another embodiment, the peptide may include the following structural formula:
-(Lys Phe Ala Lys Lys Ile 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 Ile Ala)3
(SEQ ID NO;90). In accordance with another embodiment, the peptide is
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 another ambodiment, the peptide includes the following basic structure X50:
R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41
R41 is a hydrophobic amino acid, and R42 is a basic
hydrophilic or neutral hydrophilic amino acid.
In one embodiment, the peptide includes the basic structure
Y50 -X50 wherein X50 is as hereinabove described and Y50 is:
(i) R41;
(ii) R42-R41; or
(iii) R42-R42-R41, wherein R 41 and R 42 are as
hereinabove described.
In one embodiment, R 41 is leucine. In another embodiment, R 42 is lysine. Representative examples of peptides in accordance with this aspect of the present invention include those having the following structures:
(SEQ ID NO: 95)
(SEQ ID NO: 96)
(SEQ ID NO:97)
(SEQ ID NO:98)
In accordance with another embodiment, the peptide includes the following basic structure X52:
R42-R41-R42-R42-R41-R41-R42- R42-R41-R42-R42, wherein R41 is a hydrophopbic amino acid and R 42 is a basic hydrophilic or neutral hydrophilic amino acid.
In one embodiment R41 is leucine. In another embodiment,
R42 is lysine. In one embodiment, the peptide includes the basic structure Y52 -X52, wherein X52 is as hereinabove described, and Y52 is:
(i) R42;
(ii) R41-R42;
(iii) R41-R41-R42;
(iv) R42-R41-R41-R42;
(v) R42-R42-R41-R41-R42.
In one emodiment, the peptide may have the following structure;
Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu
5 10
Leu Lys Lys Leu Arg Arg
15
(SEQ ID NO:99)
In another embodiment, the peptide includes the basic structure X52-Z52, wherein X52 is as hereinabove described, and
Z52 is:
(i ) R41;
(ii) R41-R41;
(iii) R41-R41-R42 ;
(iv) R41-R41-R42-R42; or
(v) R41-R41-R42-R42-R41;
In one embodiment, the peptide may have the following structure:
Lys Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu
5 10 15
(SEQ ID NO: 100)
In another embodiment, the peptide may include the
structure:
(Y52)a - X52 - (Z52)b, wherein X52, Y52, and Z52 are as hereinabove described, and a is 0 or 1, and b is 0 or 1.
In accordance with another embodiment, the peptide includes the following basic structure X54:
R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R43, wherein R41 and R42 are as hereinabove described, and R43 is a netural hydrophilic amino acid.
In one embodiment, the peptide may have the following structure :
(SEQ ID NO: 101)
In another embodiment, the peptide may have the following structure:
(SEQ ID NO: 102)
In accordance with yet another embodiment, the peptide includes the following basic structure X56:
R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44' wherein R41 and R42 are as hereinabove described, and R44 is a neutral hydrophilic amino acid or proline.
In one embodiment, the peptide may include the following structure Y56-X56, wherein X56 is the basic peptide structure hereinabove described, and Y56 is:
(i) -R41
(ii) -R41-R41;
(iii) - R42-R41-R41;
(iv) -R41-R42-R41-R41;
(v) -R41-R41-R42-R41-R41;
(vi) - R42-R41-R41-R42-R41-R41; or
(vii) -R42- R42-R41-R41-R41-R42-R41-R41,
wherein R41 and R42 are as hereinabove described.
In one embodiment, the peptide may include the structure:
X56-Z56, wherein X56 is as hereinabove described, and Z56 is:
(i) -R42;
(ii) -R42-R42;
(iii) -R42-R42-R41.
(iv) -R42-R42-R41-R41;
(v) -R42-R42-R41-R41-R42;
(vi) -R42-R42-R41-R41-R42-R42; or
(vii) -R42-R42-R41-R41-R42-R42-R41. In a preferred embodiment, the peptide may have one of the following structures:
(SEQ ID NO: 103); or
(SEQ ID NO:104).
In another emodiment, the peptide may have the structure (Y56) -X56-(Z56)b, wherein X56, Y56, and Z56 are as hereinabove described, a is 0 or 1, and b is 0 or 1.
In accordance with another embodiment, the peptide includes the following basic structure X58 :
R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R43'
wherein R41, R42 and R43 are as hereinabove described.
In accordance with another embodiment, the peptide may include the structure Y58-X58, wherein X58 is as hereinabove described, and X58 is:
(i) - R41;
( i i ) - R42-R41;
(iii) - R42- R42-R41;
(iv) - R41- R42-R42-R41;
(V) -R41-R41-R42-R42-R41;
(vi) -R42-R41-R41-R42-R42- R41; or
(vii) -R42-R42-R41-R41-R42-R42-R41' wherein R41 and R42 are as hereinabove described.
In another embodiment, the peptide includes the structure X58-Z58, wherein X58 is as hereinabove described, and Z58 is:
(i) -R41;
(ϋ) -R41-R45;
(iii) -R41-R45-R45;
(iv) -R41-R45-R45-R43;
(V) -R41-R45-R45-R43-R41;
(vi) - R41-R45-R45-R43- R41-R43;
(vii) -R41-R45-R45-R43-R41-R43-R43;
(viii) -R41-R45-R45-R43-R41-R43-R43'-R45; or
(ix) -R41-R45-R45-R43-R41-R43-R43'-R45-R43' wherein R41 and R43 are as hereinabove described, and R45 is proline.
In one embodiment, the peptide has the following structure: In one embodiment, the peptide may have the structure
(Y58)a-X58-(Z58)b, wherein X58, Y58, and Z58 are as hereinabove described, a is 0 or 1, and b is 0 or 1.
In accordance with another embodiment, the peptide includes the following basic structure X60;
R41- R41-R43- R42-R41- R41- R41- R41- R41- R41- R42- R41- R41- R42- R42- R41"
R41-R42-R42-R42-R41' wherein R41, R42, and R43 are as hereinabove described. In one embodiment, the peptide may have the following structure:
(SEQ ID NO: 106).
In another embodiment, the peptide may include the structure X60-Z60' wherein X60 is as hereinabove described, and Z60 is:
( i ) -R42 ;
( ii) -R42 -R42 ;
( iii ) -R42-R42-R41 ;
(iv) -R42-R42-R41-R41;
(V) - R42- R42- R41-R41- R42;
(vi) -R42-R42-R41-R41-R42-R42; or
(vii) -R42- R42- R41-R41- R42- R42- R41.
In accordance with yet another embodiment, the peptide has a structure selected from the group consisting of:
(a) R41-R42-R42-R41- R42-R42- R41;
(h) R41-R41- R42-R42-R41- R42-R42- R41;
(c) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(d) R42- R42-R41- R41- R42- R42- R41- R42- R42-R41; and
(e) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41, wherein R41 and R42 are as hereinabove described.
In one embodiment, the peptide has the structure (a), and a representative example of such a structure is (SEQ ID NO: 107), which is given in the accompanying sequence listing.
In another embodiment, the peptide has the structure (b), and a representative example of such a structure is (SEQ ID
NO: 108), which is given in the accompanying sequence listing. In another embodiment, the peptide has the structure (c), and a representative example of such a structure is (SEQ ID NO: 109) as given the accompanying sequence listing.
In yet another embodiment, the peptide has the structure (d), and a representative example of such a structure is (SEQ ID NO: 110) as given in the accompanying sequence listing.
In a further embodiment, the peptide has the structure (e), and representative examples of such a structure are (SEQ ID NO: 111) and (SEQ ID NO: 112) as given in the accompanying sequence listing.
In accordance with another embodiment, the peptide has the following structural formula:
(SEQ ID NO: 113).
In accordance with yet another embodiment, the peptide may be a cecropin or sarcotoxin.
The term cecropins includes the basic structure as well as analogues and derivatives thereof. The cecropins and analogues and derivatives thereof are described in Ann. Rev. Microbiol.
1987, Vol. 41, pages 103-26, in particular page 108, and in
Christensen, et al., PNAS Vol. 85, pgs. 5072-76, which are hereby incorporated by reference.
The term sarcotoxins includes the basic materials as well as analogues and derivatives thereof. The sarcotoxins and analogues and derivatives thereof are described in Molecular Entomology, pages 369-78, in particular page 375, Alan R. Liss, Inc. (1987), which is hereby incorporated by reference.
Ion channel-forming proteins or peptides which may be employed include defensins, also known as human neutrophil antimicrobial peptides (HNP), major basic protein (MBP) of eosinophils, bactericidal permeability-increasing protein (BPI), and a pore-forming cytotoxin called variously perforin, cytolysin, or pore-forming protein. Defensins are described in Selsted, et al., J. Clin. Invest., Vol. 76, pgs. 1436-1439
(1985). MBP proteins are described in Wasmoen, et al., J. Biol. Chem., Vol. 263, pgs 12559-12563. (1988). BPI proteins are described in Ooi, et al, J. Biol. Chem., Vol. 262, pgs.
14891-14894 (1987). Perforin is described in Henkart, et al., J. Exp. Med., 160: 75 (1984), and in Podack, et al., J. 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 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 one which when introduced into a target cell, virus, or virally-infected cell, inhibits and/or prevents and/or destroys the growth of the target cell, virus, or virally-infected 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 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 ion having pharmacological properties. As representative examples of ions having
pharmacological properties which may be employed, there may be mentioned fluoride, peroxide, bicarbonate, and silver ions. 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 the target cell, virus, or virally-infected cell. 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 or a target cell, virus, or virally-infected cell.
The ion having pharmacological properties, when used
topically, is generally employed in a concentration of from 0.05% to 2.0%. When used systemically, the ion is generally employed in an amount of from 1 to 10 mg. per kg. of host weight. Peptide or protein dosages may be within the ranges hereinabove
described.
It is also to be understood that the peptide or protein and ion may be delivered or administered in different forms; for example, the ion may be administered orally, while the peptide or protein may be administered by IV or IP.
As representative examples of administering the peptide or protein and ion for topical or local administration, the peptide or protein could be administered in an amount of up to about 1% weight to weight and the ion delivered in an amount of about 50mM (about 0.1%). Alternatively, the ion, in the form of a salt such as sodium fluoride, could be administered orally in conjunction with systemic administration of the peptide. For example, the peptide or protein may be administered IV or IP to achieve a serum dose of 100 micrograms per milliliter (10 milligrams per kilogram) in conjunction with an oral dose of ion, in particular, sodium fluoride, of 10 meq per kilogram.
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, gramacidin, polymyxin, vancomycin, teichoplanin, aminoglycosides, hydrophobic antibiotics,
penicillins, monobactams, or derivatives or analogues thereof.
The bacitracins, gramacidin, polymyxin, vancomycin, and teichoplanin, and derivatives and analogues thereof, are a group of polypeptide antibiotics. A preferred bacitracin is bacitracin A.
Aminoglycoside antibiotics include tobramycin, kanamycin, amikacin, the gentamicins (e.g., gentamicin C1, gentamicin C2, gentamicin Cl a), 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, ampicillin, methicillin
(dimethoxyphenyl penicillin), ticaricillin, penicillin V
(phenoxymethyl penicillin), σxacillin, cloxacillin,
dicloxacillin, flucloxacillin, amoxicillin, and amidinocillin. Preferred penicillins which may be employed are benzyl penicillin and ampicillin. A preferred monobactam 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 erythromycin, roxythromycin, clarithromycin, etc.; 9-N-alkyl derivatives of erythromycin; midecamycin acetate; azithromycin; flurithromycin; rifabutin; rokitamycin; a
6-O-methyl erythromycin A known as.TE-031 (Taisho); rifapentine; benzypiperazinyl rifamycins such as CGP-7040, CGP-5909,
CGP-279353 (Ciba-Geigy); an erythromycin A derivative with a cyclic carbamate fused to the C11/C12 Position of a macrolide ring known as A-62514 (Abbott); AC-7230 (Toyo Jozo);
bbYenzoxazinorifamycin; difficidin; dirithromycin; a
3-N-piperdinomethylzaino methyl rifamycin SV known as FCE-22250 (Farmitalia); M-119-a (Kirin Brewery); a
6-O-methyl-1-4"-O-carbamoyl erythromycin 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-O-alpha-L-cladinosyl moiety, such as 3-O-alpha-L-cladinosyldeepoxy rosaramicin; 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 ribosome inhibitors such as lincomycin; clindamycin; and chloramphenicol; etc.;
antibiotics which have a large lipid like lactone ring, such as mystatin; pimaricin, etc.
The peptide or protein and antibiotic may be adminstered by direct administration to a target cell or by systemic or topical administration to a host which includes the target cell, in order to prevent, destroy or inhibit the growth of a target cell.
Target cells whose growth may be prevented, inhibited, or destroyed by the administration of the peptides and antibiotic include Gram-positive and Gram-negative bacteria as well as fungal cells.
The antibiotic, such as those hereinabove described, or derivatives or analogues thereof, when used topically, is
generally employed in a concetration of about 0.1% to about 10%. When used systemically, the antibiotic or derivative or analogue thereof is generally employed in an amount of from 1.25 mg. to about 45 mg. per kg. of host weight per day. Peptide or protein dosages may be those as hereinabove described.
As representative exmples of administering the peptide or protein and antibiotic for topical or local administration, the peptide or protein could be administered in an amount of from about 0.1% to about 10% weight to weight, and the antibiotic is delivered in an amount of from about 0.1% to about 10% weight to weight. In accordance with another embodiment, the peptides or proteins of the present invention may be administered in
combination with an antiparasitic agent or an antifungal agent.
Antiparasitic agents which may be employed include, but are not limited to, anti-protozoan agents. Examples of specific anti-parasitic agents which may be employed include, but are not limited to, pentamidine isethionate, and propamidine isethionate (Brolene).
Anti-fungal agents which may be employed include, but are not limited to, ketoconazole. It is also to be understood that certain anti-parasitic agents, may also have anti-fungal
activity, and that certain anti-fungal agents may have
anti-parasitic activity.
In accordance with another embodiment, the peptides or proteins of the present invention may be administered in
combination with an antibiotic which inhibits DNA gyrase, which is an enzyme involved in the formation of bonds between
individual coiling strands of replicating bacterial DNA. Thus, DNA gyrase is necessary for the normal replication of bacterial DNA, and, therefore, antibiotics which inhibit DNA gyrase inhibit the normal replication of bacterial DNA.
Examples of antibiotics which inhibit DNA gyrase include nalidixic acid, oxolinic acid, cinoxacin, and quinolone
antibiotics which include ciprofloxacin, norfloxacin, ofloxacin, enoxacin, pefloxacin, lomefloxacin, fleroxacin, tosulfloxacin, temafloxacin, and rufloxacin.
In accordance with another embodiment, the peptides or proteins of the present invention may be administered for the purposes hereinabove described in combination with one another.
The invention will now be further described with respect to the following examples; however, the scope of the present
invention is not to be limited thereby.
Example 1 - Antibacterial Assay The procedure for the following antibacterial assay is based upon the guidelines of the National Committee for Clinical
Laboratory Standards, Document M7-T2, Volume 8, No. 8, 1988.
Stock solutions of the following Peptides 1, 2, and 3 are prepared at a concentration of 512 μg/ml in sterile deionized distilled water and stored at -70°C.
Peptide 1 has the following structural formula:
(SEQ ID NO:27)-NHCH2CH2OH.
Peptide 2 has the following structural formula:
(SEQ ID NO:27)-NHCH2CH2NH2.
Peptide 3 has the following structural formula:
(SEQ ID NO:27)-NH2.
The stock peptide solution is diluted in serial dilutions (1:2) down the wells of a microtiter plate so that the final concentrations of peptides in the wells are 0.25, 0.50, 1, 2, 4, 8, 16, 32, 64, 128, and 256 μg/ml. 1-5 × 105 CFUs/ml of either S. aureus ATCC 25923, E. coli ATCC 25922, or P. aeruginosa ATCC 27853 were added to the wells in full strength Mueller Hinton broth (BBL 11443) from a mid-log culture. The inoculum is standarized spectrophotometrically at 600nm and is verified by colony counts. The plates are incubated for 16-20 hours at 37°C, and the minimal inhibitory concentration (MIC) for each peptide is determined. Minimal inhibitory concentration is defined as the lowest concentration of peptide which produces a clear well in the microtiter plate. The results are given in Table I below.
For purposes of explanation of Table I below, S is the MIC of the peptide against S .aureus, P is the MIC of the peptide against P. aeruginosa, and E is the MIC of the peptide against
E.coli.
TABLE I
Peptide MIC (uq/ml)
S P E
1 4,8 32 4
2 16 64, 128 4
3 I6 64, 128 4 The above results indicate that a biologically active peptide having a C-terminal ethanolamine group provided increased biological activity as opposed to the same peptide having an unsubstituted C-terminal amide.
The peptides or proteins of the present invention, whether administered alone or in combination with agents such as toxic ions, antibotics, or other biologically active peptides or proteins as hereinabove described, may be employed in a wide variety of pharmaceutical compositions in combination with a non-toxic pharmaceutical carrier or vehicle such as a filler; non-toxic buffer, or physiological saline solution. Such
pharmaceutical compositions may be used topically or systemically and may be in any suitable form such as a liquid, solid,
semi-solid, injectable solution, tablet, ointment, lotion, paste, capsule or the like. The peptide or protein and/or agent as hereinabove described may also be used in combination with adjuvants, protease inhibitors, or compatible drugs where such a combination is seen to be desirable or advantageous in
controlling infection caused by harmful microorganisms including protozoa, viruses, parasites, fungi, and the like.
The peptide or protein may be administerd to a host in particular an animal, in an effective antibiotic and/or
anti-tumor and/or antiviral and/or antimicrobial and/or
antispermicidal and/or antifungal and/or antiparasitic amount, or in an amount effective to stimulate wound healing in a host. The peptides or proteins may be administerd either alone or in combination with an ion having pharmacological properties, antibiotic, or ion channel forming peptide or protein as
hereinabove described. When the peptide or protein is
administered in combination with an ion having pharmacological properties, the activity of the peptide or protein is
potentiated.
When the peptide or protein is administered in combination with an agent as hereinabove described, it is possible to administer the peptide or protein and agent in separate forms. For example, the agent may be administered systemically and the peptide or protein may be administered topically.
When the peptide or protein is adminitered topically, it may be administered in combination with a water-soluble vehicle, said water-soluble vehicle being in the form of an ointment, cream, lotion, paste or the like. Examples of water-soluble vehicles which may be employed include, but are not limited to, glycols, such as polyethylene glycol, hydroxycellulose, and KY Jelly. The water-soluble vehicle is preferably free of an oily substance.
The peptide or protein may also be employed in combination with a toxic ion as hereinabove described in the form of an oral composition for oral hygiene. Such a 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 composition 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 and toxic ion may be used to inhibit, prevent, or destroy the growth of Streptococcus mutans, which is associated with dental caries and periodontal disease.
Numerous modifications and variations of the present
invention are possible in light of the above teachings and, therefore, within the scope of the accompanying claims, the invention may be practiced other than as particularly described.
SEQUENCE LISTING
(1) GENERAL INFORMATION:
(i) APPLICANT: Kari, U. Prasad
Maloy, W. Lee
(ii) TITLE OF INVENTION: Composition and Treatment with Biologically Active Peptides Having C-Terminal Substitutions
(iii) NUMBER OF SEQUENCES: 113
(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: 07713716
(B) FILING DATE: 12-JUN-1991
(C) CLASSIFICATION: (vii) PRIOR APPLICATION DATA:
(A) APPLICATION NUMBER:
(B) FILING DATE:
(viii) ATTORNEY/AGENT INFORMATION:
(A) NAME: Olstein, Elliot M.
(B) REGISTRATION NUMBER: 24,025
(C) REFERENCE/DOCKET NUMBER: 421250-119
(ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 201-994-1700
(B) TELEFAX: 201-994-1744
(2) INFORMATION FOR SEQ ID NO:1:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 20 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(x) PUBLICATION INFORMATION:
(H) DOCUMENT NUMBER: W089/11290
(I) FILING DATE: 19-MAY-1989
(J) PUBLICATION DATE: 30-NOV-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:
Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe
5 10
Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys
15 20
(2) INFORMATION FOR SEQ ID NO:2: (i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 24 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS :
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(x) PUBLICATION INFORMATION:
(H) DOCUMENT NUMBER: W089/11290
(I) FILING DATE: 19-MAY-1989
(J) PUBLICATION DATE: 30-NOV-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:2: Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe
5 10
Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys
15 20
Ala Phe Ser Lys
(2) INFORMATION FOR SEQ ID NO: 3:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide
(x ) PUBLICATION INFORMATION:
(H) DOCUMENT NUMBER: W089/11290
( I ) FILING DATE : 19-MAY-1989
( J) PUBLICATION DATE : 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3: Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser
5 10
Lys Ala Phe Ser Lys Ala
15
(2) INFORMATION FOR SEQ ID NO: 4:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 20 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(x) PUBLICATION INFORMATION:
(H) DOCUMENT NUMBER: W089/11290
(I) FILING DATE: 19-MAY-1989
(J) PUBLICATION DATE: 30-NOV-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 4: Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys
5 10
Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe
15 20
(2) INFORMATION FOR SEQ ID NO: 5:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii ) MOLECULE TYPE : peptide (x) PUBLICATION INFORMATION:
(H) DOCUMENT NUMBER: W089/11290
(I) FILING DATE: 19-MAY-1989
(J) PUBLICATION DATE: 30-N0V-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 5: Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala
5 10
Phe Ser Lys Ala Phe Ser
15
(2) INFORMATION FOR SEQ ID NO: 6:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 23 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: Magainin I peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Zasloff, Michael
(C) JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84
(F) PAGES: 5449-5453
(G) DATE: AUO - 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 Ile Gly Lys Phe Leu His Ser Ala Gly
5 10
Lys Phe Gly Lys Ala Phe Val Gly Glu Ile
15 20
Met Lys Ser
(2) INFORMATION FOR SEQ ID NO: 7:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 23 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: Magainin II peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Zasloff, Michael
(C) JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84
(F) PAGES: 5449-5453
(G) DATE: AUG - 1987
(H) DOCUMENT NUMBER: US 4810777
( I ) FILING DATE : 04-MAR-1987
(J) PUBLICATION DATE : 07-MAR-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 7 Gly Ile Gly Lys Phe Leu His Ser Ala Lys
5 10
Lys Phe Gly Lys Ala Phe Val Gly Glu Ile
15 20
Met Asn Ser
(2) INFORMATION FOR SEQ ID NO: 8:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 22 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: Magainin III peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Zasloff, Michael
(C) JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84
(F) PAGES: 5449-5453
(G) DATE: AUG - 1987
(H) DOCUMENT NUMBER: US 4810777
( I ) FILING DATE : 04-MAR-1987
( J) PUBLICATION DATE : 07-MAR-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 8 Gly Ile Gly Lys Phe Leu His Ser Ala Lys
5 10
Lys Phe Gly Lys Ala Phe Val Gly Glu Ile
15 20
Met Asn
(2) INFORMATION FOR SEQ ID NO: 9:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 22 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: magainin peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Zasloff, Michael
(C) JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84
(F) PAGES: 5449-5453
(G) DATE: AUG - 1987
(H) DOCUMENT NUMBER: US 4810777
( I ) FILING DATE : 04-MAR-1987
(J) PUBLICATION DATE : 07-MAR-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 9: Ile Gly Lys Phe Leu His Ser Ala Lys Lys
5 10
Phe Gly Lys Ala Phe Val Gly Glu Ile Met
15 20
Asn Ser
(2) INFORMATION FOR SEQ ID NO: 10:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: magainin peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Zasloff, Michael
(C) JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84
(F) PAGES: 5449-5453
(G) DATE: AUG - 1987
(H) DOCUMENT NUMBER: US 4810777
( I ) FILING DATE : 04-MAR-1987
( J) PUBLICATION DATE : 07-MAR-1989
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 10: Gly Lys Phe Leu His Ser Ala Lys Lys Phe
5 10
Gly Lys Ala Phe Val Gly Glu Ile 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 Ile Met Asn Ser
15 20 (2) INFORMATION FOR SEQ ID NO: 12:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: PGLa peptide.
(x) PUBLICATION INFORMATION:
(A ) AUTHOR: Hoffman, et al.
(C ) JOURNAL: EMBO J.
(D ) VOLUME: 2
(F ) PAGES: 711-714
(G ) DATE: 1983
(A) AUTHOR: Andreu, et al.
(C) JOURNAL: Journal of Biochemistry
(D) VOLUME: 149
(F) PAGES: 531-535
(G) DATE: 1985
(A) AUTHOR: Gibson, et al.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(A) AUTHOR: Giovannini, et al.
(C) JOURNAL: Biochem J.
(D) VOLUME: 243
(F) PAGES: 113-120
(G) DATE: 1987 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 12. Gly Met Ala Ser Lys Ala Gly Ala Ile Ala
5 10
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala
15 20
Leu
(2) INFORMATION FOR SEQ ID NO: 13:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 25 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: XPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Hoffman, et a1.1
(C) JOURNAL: EMBO J.
(D) VOLUME: 2
(F) PAGES: 711-714
(G) DATE: 1983
(A) AUTHOR: Andreu, et al.
(C) JOURNAL: Journal of Biochemistry
(D) VOLUME: 149
(F) PAGES: 531-535
(G) DATE: 1985
(A) AUTHOR: Gibson, et al.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349 ( G) DATE : 1986
(A) AUTHOR: Giovannini, et al.
(C) JOURNAL: Biochem J.
(D) VOLUME: 243
(F) PAGES: 113-120
(G) DATE: 1987
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 13: Gly Trp Ala Ser Lys Ile Gly Gln Thr Leu
5 10
Gly Lys Ile Ala Lys Val Gly Leu Lys Glu
15 20
Leu Ile Gln Pro Lys
25
(2) INFORMATION FOR SEQ ID NO: 14:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680 (G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S .
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(H) DOCUMENT NUMBER: W090/04407
(I) FILING DATE: 16-OCT-1989
(J) PUBLICATION DATE: 03-MAY-1990
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 14: Gly Phe Gly Ser Phe Leu Gly Leu Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala
15 20
Leu Gly Gly Ala Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 15:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY : CPF peptide .
( x ) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME : 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES : 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES : 5341-5349
(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 Ile Gly Ala His Leu
15 20
Leu Gly Gly Ala Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 16:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES : 1817-1828 (G) DATE : 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(H) DOCUMENT NUMBER: W090/04407
(I) FILING DATE: 16-OCT-1989
(J) PUBLICATION DATE: 03-MAY-1990
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 16: Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu
5 10
Lys Ala Gly Leu Lys Ile Gly Thr His Phe
15 20
Leu Gly Gly Ala Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 17:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION: (A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES : 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES : 5341-5349
(G) DATE: 1986
(H) DOCUMENT NUMBER: W090/04407
(I) FILING DATE: 16-OCT-1989
(J) PUBLICATION DATE: 03-MAY-1990
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 17:
Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu
5 10
Lys Ala Thr Leu Lys Ile Gly Thr His Phe
15 20
Leu Gly Gly Ala Pro Gln Gln
25 (2) INFORMATION FOR SEQ ID NO: 18:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S .
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B . W.
Poulter, L .
Williams , D . H.
Maggio , J . E .
(C) JOURNAL: J . Biol . Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349 ( G) DATE : 1986
(H) DOCUMENT NUMBER: W090/04407
(I) FILING DATE: 16-OCT-1989
(J) PUBLICATION DATE: 03-MAY-1990
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 18: Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Met
15 20
Leu Gly Gly Thr Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 19:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi , T . Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(H) DOCUMENT NUMBER: W090/04407
(I) FILING DATE: 16-OCT-1989
(J) PUBLICATION DATE: 03-MAY-1990
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 19: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala
15 20
Leu Gly Gly Ala Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO:20:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide ( ix) FEATURE :
(A) NAME/KEY: CPF peptide.
(X) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(H) DOCUMENT NUMBER: W090/04407
(I) FILING DATE: 16-OCT-1989
(J) PUBLICATION DATE: 03-MAY-1990 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 20: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala
15 20
Leu Gly Gly Ser Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 21:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
( F) PAGES : 1817-1828 (G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(H) DOCUMENT NUMBER: W090/04407
(I) FILING DATE: 16-OCT-1989
(J) PUBLICATION DATE: 03-MAY-1990
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21: Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Leu
15 20
Leu Gly Gly Thr Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 22:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide .
(x) PUBLICATION INFORMATION: (A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:
Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala
15 20
Leu Gly Gly Ala Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 23:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H. Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES : 5341-5349
(G) DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 23: Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Met
15 20
Leu Gly Gly Ala Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO:24:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
( ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
( F) PAGES : 1817-1828 (G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES : 5341-5349
(G) DATE: 1986
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 24: Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala
15 20
Leu Gly Gly Ser Leu Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 25:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S.
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 25
Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu
5 10
Lys Ala Gly Leu Lys Ile Gly Thr Asn Phe
15 20
Leu Gly Gly Ala Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 26:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(A) NAME/KEY: CPF peptide.
(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K
Egger, R.
Kreil
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 261
(F) PAGES: 3676-3680
(G) DATE: 1986
(A) AUTHOR: Wakabayashi, T.
Kato, H.
Tachibaba, S .
(C) JOURNAL: Nucleic Acids Research
(D) VOLUME: 13
(F) PAGES: 1817-1828
(G) DATE: 1985
(A) AUTHOR: Gibson, B .W.
Poulter, L.
Williams , D.H. Maggio, J. E .
(C) JOURNAL: J. Biol . Chem.
(D) VOLUME: 261
(F) PAGES: 5341-5349
(G) DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 26:
Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu
5 10
Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala
15 20
Leu Gly Gly Ser Pro Gln Gln
25
(2) INFORMATION FOR SEQ ID NO: 27:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:27: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile
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 Ile Ala Lys Ile Ala Gly Lys Ile Ala
5 10
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
15 20
Gly
(2) INFORMATION FOR SEQ ID NO:29:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:29: Lys Ile Ala Gly Lys Ile Gly Lys Ile Ala
5 10
Gly Lys Ile Gly Lys Ile Ala Gly Lys Ile
15 20
Gly
(2) INFORMATION FOR SEQ ID NO:30:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii ) MOLECULE TYPE : peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 30:
Lys Leu Ala Gly Lys Leu Ala Lys Leu Ala
5 10
Gly Lys Leu Ala Lys Leu Ala Gly Lys Leu
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 31:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 31:
Lys Phe Ala Gly Lys Phe Ala Lys Phe Ala
5 10
Gly Lys Phe Ala Lys Phe Ala Gly Lys Phe
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 32:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 32: Lys Ala Leu Ser Lys Ala Leu Lys Ala Leu
5 10
Ser Lys Ala Leu Lys Ala Leu Ser Lys Ala
15 20
Leu
(2) INFORMATION FOR SEQ ID NO:33:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 33: Lys Leu Leu Lys Ala Leu Gly Lys Leu Leu
5 10
Lys Ala Leu Gly Lys Leu Leu Lys Ala Leu
15 20
Gly
(2) INFORMATION FOR SEQ ID NO: 34:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii ) MOLECULE TYPE : peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 34: Lys Ala Ile Gly Lys Ala Ile Lys Ala Ile
5 10
Gly Lys Ala Ile Lys Ala Ile Gly Lys Ala
15 20
Ile
(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 Ile Ala Lys Ile Ala Lys Gly Ile Ala
5 10
Lys Ile Ala Lys Gly Ile Ala Lys Ile Ala
15 20
Lys
(2) INFORMATION FOR SEQ ID NO: 36:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 36:
Lys Ile Ala Lys Ile Phe Gly Lys Ile Ala
5 10
Lys Ile Phe Gly Lys Ile Ala Lys Ile Phe
15 20
Gly
(2) INFORMATION FOR SEQ ID NO: 37:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:37: Gly Ile Ala Arg Ile Ala Lys Gly Ile Ala
5 10
Arg Ile Ala Lys Gly Ile Ala Arg Ile Ala
15 20
Lys
(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 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 38: Lys Phe Ala Arg Ile Ala Gly Lys Phe Ala
5 10
Arg Ile Ala Gly Lys Phe Ala Arg Ile 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 Ile Ala Lys Gly Phe Ala
5 10
Lys Ile Ala Lys Gly Phe Ala Lys Ile 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 i s ornithine (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 40: Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala
5 10
Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 41:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:41: Lys Ile Ala Arg Ile Ala Gly Lys Ile Ala
5 10
Arg Ile Ala Gly Lys Ile Ala Arg Ile Ala
15 20
Gly
(2) INFORMATION FOR SEQ ID NO:42:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is ornithine (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 42: Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala
5 10
Gly Lys Ile Ala Xaa Ile Ala Gly Lys Ile
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 Ile Ala Arg Ile Phe Lys Gly Ile Ala
5 10
Arg Ile Phe Lys Gly Ile Ala Arg Ile Phe
15 20
Lys
(2) INFORMATION FOR SEQ ID NO: 44:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION : Xaa is norleucine (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 44: Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala
5 10
Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 45:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 45: Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala
5 10
Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 46:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE : peptide ( ix ) FEATURE :
(D) OTHER INFORMATION: Xaa is norleucine (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 46: Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala
5 10
Gly Lys Xaa Ala Lys Ile 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
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norvaline
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 48: Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala
5 10
Gly Lys Ile Ala Lys Xaa Ala Gly Lys Xaa
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 49:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 49: Lys Leu Leu Ser Lys Leu Gly Lys Leu Leu
5 10
Ser Lys Leu Gly Lys Leu Leu Ser Lys Leu
15 20
Gly
(2) INFORMATION FOR SEQ ID NO: 50:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 50:
Lys Leu Leu Ser Lys Phe Gly Lys Leu Leu
5 10
Ser Lys Phe Gly Lys Leu Leu Ser Lys Phe
15 20
Gly
(2) INFORMATION FOR SEQ ID NO:51:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide
( ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norvaline
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 51: Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala
5 10
Gly Lys Xaa Ala Lys Ile Ala Gly Lys Xaa
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 52:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 52: His Ile Ala Gly His Ile Ala His Ile Ala
5 10
Gly His Ile Ala His Ile Ala Gly His Ile
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 Ile Ala Lys Ile Ala Gly Lys
5 10
Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys
15 20
Ile
(2) INFORMATION FOR SEQ ID NO: 54:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE : peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 54: Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys
5 10
Ile Ala Gly Lys Ile Ala Lys Ile 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 Ile Ala Gly Arg Ile Ala Lys Ile Ala
5 10
Gly Arg Ile Ala Lys Ile Ala Gly Arg Ile
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 Ile Ala Gly Arg Ile Ala Arg Ile Ala
5 10
Gly Arg Ile Ala Arg Ile Ala Gly Arg Ile
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 Ile Ala Lys Val Ala
5 10
Gly Lys Ile Ala Lys Val Ala Gly Lys Ile
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 Ile Ala Gly Lys Val Ala Lys Ile Ala
5 10
Gly Lys Val Ala Lys Ile Ala Gly Lys Val
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 59:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 59: Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile
5 10
Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys
15 20
Ile
(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 (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 60: Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala
5 10
Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO:61:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 61: Lys Phe Ala Gly Lys Ile Ala Lys Phe Ala
5 10
Gly Lys Ile Ala Lys Phe Ala Gly Lys Ile
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 Ile Ala Gly Lys Phe Ala Lys Ile Ala
5 10
Gly Lys Phe Ala Lys Ile Ala Gly Lys Phe
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 63:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is cyclohexylalanine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 63:
Lys Xaa Ala Gly Lys Ile Ala Lys Xaa Ala
5 10
Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ile
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 Ile Ala Gly Lys Xaa Ala
5 10
Lys Ile Ala Gly Lys Xaa Ala Lys Ile 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 Ile Ala Gly Lys Ile Ala Arg Ile Ala
5 10
Gly Lys Ile Ala Arg Ile Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 66:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii ) MOLECULE TYPE : peptide ( ix) FEATURE :
(D) OTHER INFORMATION: Xaa is homoarginine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 66:
Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala
5 10
Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 67:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE: Xaa is p-aminophenylalanine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 67:
Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala
5 10
Gly Lys Ile Ala Xaa Ile Ala Gly Lys Ile
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) MOLECULRE TYPE: peptide
(ix) FEATURE: Xaa is p-aminophenylalanine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 68: Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala
5 10
Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 69:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 24 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 69: Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala
5 10
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
15 20
Gly Lys Ile 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 lie Ala Gly
5 10
Lys Ile Ala Lys Val Ala Leu Lys Ala Leu
15 20
(2) INFORMATION FOR SEQ ID NO: 71:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is ornithine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 71:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly
5 10
Xaa Ile Ala Lys Ile Ala Gly Lys Ile 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 Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Arg Ile Ala Lys Ile Ala Gly Lys Ile
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
(xi) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 73:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 74:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norvaline (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 74:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 75:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is ornithine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 75:
Lys Phe Ala Gly Lys Phe Ala Lys Phe Ala Gly
5 10
Xaa Phe Ala Lys Phe Ala Gly Lys Phe Ala
15 20
(2) INFORMATION FOR SEQ ID NO: 76:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide
( ix) FEATURE : (D) OTHER INFORMATION: Xaa is ornithine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 76:
Lys Ile Ala Gly Lys Phe Ala Lys Ile Ala
5 10
Gly Xaa Phe Ala Lys Ile Ala Gly Lys Phe
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 77:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa at residues 6, 13, and 20 is norleucine, Xaa at residue
12 is ornithine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 77:
Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala
5 10
Gly Xaa Xaa Ala Lys Ile 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 Ile Ala
5 10
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala
15 20
Leu
(2) INFORMATION FOR SEQ ID NO: 79:
(i.) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 79:
Lys Ile Ala Ser Lys Ala Gly Lys Ile Ala
5 10
Gly Lys Ile 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 Ile Ala Ser Lys Ala Gly Lys Xaa Ala
5 10
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu
15 20
(2) INFORMATION FOR SEQ ID NO: 81:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii ) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:
Lys Leu Ala Ser Lys Ala Gly Lys Xaa Ala
5 10
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala
15 20
Leu
(2 ) INFORMATION FOR SEQ ID NO: 82 :
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 82:
Lys Xaa Ala Ser Lys Ala Gly Lys Xaa Ala
5 10
Gly Lys lie Ala Lys Val Ala Leu Lys Ala Leu
15 20
(2) INFORMATION FOR SEQ ID NO: 83:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: Xaa is p-aminophenylalanine.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 83:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile
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 Ile Ala Gly Ala Ile Ala Lys Ile Ala
5 10
Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 85:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 85: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Ala Ile Ala Lys Ile Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO:86:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids (B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 86: Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Lys Ile Ala Lys Ile Ala Gly Ala Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 87:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 87: Lys Leu Ala Ser Lys Ala Ala Lys Ile Ala
5 10
Ala Lys Ile Ala Lys Val Ala Leu Lys Ala
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 Ile Ala Lys Lys Ile Ala Lys Ile Ala
5 10
Lys Lys Ile Ala Lys Ile Ala Lys Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO:89:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 89: Lys Phe Ala Lys Lys Phe Ala Lys Phe Ala
5 10
Lys Lys Phe Ala Lys Phe Ala Lys Lys Phe
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 90:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii ) MOLECULE TYPE : peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90: Lys Phe Ala Lys Lys Ile Ala Lys Phe Ala
5 10
Lys Lys Ile Ala Lys Phe Ala Lys Lys Ile
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 Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 92:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
( ii ) MOLECULE TYPE : peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92: Lys Ile Ala Gly Lys Ile Ala Ala Ile Ala
5 10
Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile
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 Ile Ala Gly Lys Ile Ala Lys Ile Ala
5 10
Gly Lys Ile Ala Ala Ile Ala Gly Lys Ile
15 20
Ala
(2) INFORMATION FOR SEQ ID NO: 94:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO: 94: Gly Met Ala Ser Lys Ala Gly Lys Ile Ala
5 10
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala
15 20
Leu
(2) INFORMATION FOR SEQ ID NO: 95:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 95: Leu Lys Lys Leu Lys Lys Leu Leu Lys Leu
5 10
Leu
(2) INFORMATION FOR SEQ ID NO: 96:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 12 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 96: Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys
5 10
Leu Leu (2) INFORMATION FOR SEQ ID NO: 97:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 13 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 97: Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu
5 10
Lys Leu Leu
(2) INFORMATION FOR SEQ ID NO:98:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 14 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:
Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu
5 10
Leu Lys Leu Leu
(2) INFORMATION FOR SEQ ID NO:99:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 99:
Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Arg Arg
5 10 15
(2) INFORMATION FOR SEQ ID NO: 100:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 16 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 100:
Lys Leu Lys Lys Leu Leu Lys Lys Leu Lys
5 10
Lys Leu Leu Lys Leu Leu
15
(2) INFORMATION FOR SEQ ID NO: 101:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 101:
Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys
5 10
Leu Leu Lys Lys Asn
15 (2) INFORMATION FOR SEQ ID NO: 102:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 15 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(ix) FEATURE:
(D) OTHER INFORMATION: xaa is homoserine.
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 102:
Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys
5 10
Leu Leu Lys Lys Xaa
15
(2) INFORMATION FOR SEQ ID NO: 103:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 18 amino acids
(B) TYPE: 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 Lys 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
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 104: Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys
5 10
Pro Lys Lys Leu Leu Lys Lys Leu
15
(2) INFORMATION FOR SEQ ID NO: 105:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 22 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 105:
Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys
5 10
Lys Leu Gln Gly Pro Pro Gln Gly Gln Ser
15 20
Pro Gln
(2) INFORMATION FOR SEQ ID NO: 106:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 20 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS: (D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 106: Leu Ala Ser Lys Ala Gly Ala Ile Ala Gly
5 10
Lys Ile Ala Lys Lys Leu Leu Lys Lys Leu
15 20
(2) INFORMATION FOR SEQ ID NO: 107:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 7 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 107: Leu Lys Lys Leu Lys Lys Leu
5
(2) INFORMATION FOR SEQ ID NO: 108:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 8 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:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 109: Lys Leu Leu Lys Lys Leu Lys Lys Leu
5
(2) INFORMATION FOR SEQ ID NO: 110:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 10 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 110: Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu
5 10
(2) INFORMATION FOR SEQ ID NO: 111:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 111: Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu
5 10
(2) INFORMATION FOR SEQ ID NO: 112:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 11 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 112: Ala Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu
5 10
(2) INFORMATION FOR SEQ ID NO: 113:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 14 amino acids
(B) TYPE: amino acid
(C) STRANDEDNESS:
(D) TOPOLOGY: linear
(ii) MOLECULE TYPE: peptide
(xi) SEQUENCE DESCRIPTION: SEQ ID NO: 113:
Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu
5 10
Leu Lys Arg

Claims (43)

WHAT IS CLAIMED IS:
1. A C-terminal substituted peptide or protein of the formula: , wherein X is a biologically active amphiphilic peptide or protein, said peptide or protein being an ion channel-forming peptide or protein, and T is selected from the group consisting of:
(a) O-R, wherein R is a substituted or unsubstituted aliphatic, aromatic, or aralkyl group having from 1 to 10 carbon atoms;
(b) NH-NH2;
(c) NH-OH; and
(d) , wherein R' and R" are hydrogen or selected from the class consisting of group (i) and group (ii), wherein group (i) is a hydroxy-substituted aliphatic, aromatic or aralkyl group having no more than 10 carbon atoms, and group (ii) is an amino-substituted aliphatic, aromatic, aralkyl, or alkylaromatic group, and at least one of R' and R" is group (i) or group (ii).
2. The peptide of Claim 1 wherein T is NH-CH2CH2-OH.
3. The peptide of Claim 1 wherein T is NH-CH2CH2-NH2.
4. The peptide of Claim 1 wherein X is a magainin peptide.
5. The peptide of Claim 1 wherein X is a PGLa peptide.
6. The peptide of Claim 1 wherein X is an XPF peptide.
7. The peptide of Claim 1 wherein X is a CPF peptide.
8. The peptide of Claim 1 wherein X is a cecropin.
9. The peptide of Claim 1 wherein X is a sarcotoxin.
10. The peptide of Claim 1 wherein X includes one of the following basic structures X31 through X37, wherein:
X31 is -[R31-R32-R32-R33-R31-R32-R32]n-; X32 is -[R32-R32-R33-R31-R32-R32-R31]n-;
X33 is -[R32-R33-R31-R32-R32-R31-R32]n-;
X34 is -[R33-R31-R32-R32-R31-R32-R32]n-;
X35 is -[R31-R32-R32-R31-R32-R32-R33]n-;
X36 is -[R32-R32-R31-R32-R32-R33-R31]n-; and
X37 is -[R32-R31-R32-R32-R33-R31-R32]n-, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.
11. The peptide of Claim 1 wherein X includes the following basic structure X40:
R31-R32-R32-R33-R34-R32-R32-R31-R32-R32-R32-R34-R32-R32' wherein R31 is a basic hydrophilic amino acid, R32 is a
hydrophobic amino acid, R33 is a neutral hydrophilic or
hydrophobic amino acid, and R34 is a basic hydrophilic or
hydrophobic amino acid.
12. The peptide of Claim 11 wherein X includes the
following structure:
Y40-X40, wherein X40 is as hereinabove described in Claim
11, and Y40 is:
(i) R32-, or
(ii) R32-R32-; or
(iii) R34-R32-R32; or
(iv) R33-R34-R32-R32; or
(v) R32-R33-R34-R32-R32; or
(vi) R32-R32-R33-R34-R32-R32; or
(vii) R31-R32-R32-R33-R34-R32-R32.
13. The peptide of Claim 11 wherein X includes the
following structure:
X40-Z40, wherein X40 is as hereinabove described in Claim
11, and Z40 is:
(i) R31-, or
(ii) R31-R32-; or
(iii) R31-R32-R32; or (iv) R31-R32-R32-R33; or
(v) R31-R32-R32-R33-R34; or
(vi) R31-R32-R32-R33-R34-R32; or
(vii) R31-R32-R32-R33-R34-R32-R32.
14. The peptide of Claim 11 wherein X includes the
following structure:
(Y40)a-X40-(Z40)b, wherein Y40 and Z40 are as previously defined in Claims 12 and 13, a is 0 or 1, and b is 0 or 1.
15. The peptide of Claim 1 wherein X includes the following structure X50 :
-R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
16. The peptide of Claim 1 wherein X includes the following structure X52:
- R42-R41-R42- R42-R41-R41-R42-R42-R41-R42-R42, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
17. The peptide of Claim 1 wherein X includes the following structure X54:
-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42- R42-R43, wherein R41 is a hydrophobic amino acid, R42 is a basic
hydrophilic amino acid or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
18. The peptide of Claim 1 wherein X includes the following structure X56:
-R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline.
19. The peptide of Claim 1 wherein X includes the following structure X58: -R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R42-R41-R43, wherein R41 is a hydrophobic amino acid, R42 is a basic
hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
20. The peptide of Claim 1 wherein X includes the following structure X60:
-R41-R41-R43- R42-R41-R41-R41-R41-R41-R41- R42-R41-R41- R42- R42- R41-R41-R42-R42-R41, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or netural hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
21. The peptide of Claim 1 wherein X has a structure selected from the group consisting of:
(a) R41-R42-R42-R41-R42-R42-R41;
(b) R41-R41-R42-R42-R41-R42- R42-R41;
(c) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(d) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and
(e) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41, wherein R41 is a hydrophobic amino acid and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
22. A process for inhibiting the growth of a target cell, virus, or virally-infected cell in a host, comprising:
administering to a host a C-terminal substituted peptide or protein of the formula: , wherein X is a biologically active amphiphilic peptide or protein, said peptide or protein being an ion
channel-forming peptide or protein, and T is selected from the group consisting of:
(a) O-R, wherein R is a substituted or unsubstituted aliphatic, aromatic, or aralkyl group having from 1 to 10 carbon atoms;
(b) NH-NH2;
(c) NH-OH; and ( d ) , wherein R' and R" are hydrogen or selected from the class consisting of group (i) and group (ii), wherein group (i) is a hydroxy-substituted aliphatic, aromatic or aralkyl group having no more than 10 carbon atoms, and group (ii) is an amino-substituted aliphatic, aromatic, aralkyl, or alkylaromatic group, and at least one of R' and R" is group (i) or group (ii).
wherein R' and R" are hydrogen or selected from the class consisting of group (i) and group (ii), wherein
group (i) is (CH2)n-OH; and
group (ii) is (CH2)n-NH2, wherein n is from 1 to 10, and wherein at least one of R' and R" is group (i) or group (ii).
23. The process of Claim 22 wherein T is NH-CH2CH2-OH.
24. The process of Claim 22 wherein T is NH-CH2CH2-NH2.
25. The process of Claim 22 wherein X is a magainin
peptide
26. The process of Claim 22 wherein X is a PGLa peptide.
27. The process of Claim 22 wherein X is an XPF peptide.
28. The process of Claim 22 wherein X is a CPF peptide.
29. The process of Claim 22 wherein X is a cecropin.
30. The process of Claim 22 wherein X is a sarcotoxin.
31. The process of Claim 22 wherein X includes one of the following basic structures X31 through X37, wherein:
X31 is -[R31-R32-R32-R33-R31-R32-R32]n-;
X32 is -[R32-R32-R33-R31-R32-R32-R31]n-;
X33 is -[R32-R33-R31-R32-R32-R31-R32]n-;
X34 is -[R33-R31-R32-R32-R31-R32-R32]n-;
X35 is -[R31-R32-R32-R31-R32-R32-R33]n-;
X36 is -[R32-R32-R31-R32-R32-R33-R31]n-' and
X37 is -[R32-R31-R32-R32-R33-R31-R32]n, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and n is from 2 to 5.
32. The process of Claim 22 wherein the X includes the following basic structure X40:
R31-R32-R32-R33-R34-R32-R32-R31-R32-R32-R32-R34-R32-R32, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid.
33. The process of Claim 32 wherein X includes the
following structure:
Y40-X40, wherein X40 is as herienabove described in Claim
32, and Y40 is:
(i) R32-, or
(ii ) R32-R32-; or
(iii) R34-R32-R32-; or
(iv) R33-R34-R32-R32; or
(v) R32-R33-R34-R32-R32; or
(vi) R32-R32-R33-R34-R32-R32; or
(vii) R31-R32-R32-R33-R34-R32-R32.
34. The process of Claim 32 wherein X includes the
following structure:
X40-Z40, wherein X40 is as hereinabove described in Claim
32, and Z40 is:
(i) R31-; or
(ii ) R31-R32- ; or
(iii ) R31-R32-R32 ; or
( iv) R31-R32-R32-R33 ; or
(V) R31-R32-R32-R33-R34; or
(vi ) R31-R32-R32-R33-R34-R32 ; or
(vii) R31-R32-R32-R33-R34-R32-R32.
35. The process of Claim 32 wherein the peptide includes the following structure:
(Y40)a-X40-(Z40)b, wherein Y40 and Z40 are as previously defined in Claims 33 and 34, a is 0 or 1, and b is 0 or 1.
36. The process of Claim 22 wherein X includes the
following structure X50:
-R41- R42- R42-R41- R42- R42-R41-R41- R42-R41-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
37. The process of Claim 22 wherein X includes the
following structure X52:
-R42-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
38. The process of Claim 22 wherein X includes the
following structure X54:
-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R43' wherein R41 is a hydrophobic amino acid, R42 is a basic
hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
39. The process of Claim 22 wherein X includes the
following structure X56:
-R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44' wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R.. is a neutral hydrophilic amino acid or proline.
40. The process of Claim 22 wherein X includes the
following structure X58:
-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R42-R41-R43' wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
41. The process of Claim 22 wherein X includes the
following structure X60:
-R41-R41-R43-R42-R41-R41-R41-R41-R41-R41-R42-R41-R41-R42-R42-R41--R41-R42-R42-R41-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
42. The process of Claim 22 wherein X has a structure selected from the group consisting of:
(a) R41-R42-R42-R41-R42-R42-R41;
(b) R42-R41-R42-R42-R41-R42-R42-R41;
(c) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(d) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and
(e) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
43. The process of Claim 22 wherein the peptide is administered in an amount effective in inhibiting growth of a target cell, virus or virally-infected cell.
AU21615/92A 1991-06-12 1992-06-01 Composition and treatment with biologically active peptides having c-terminal substitutions Abandoned AU2161592A (en)

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AU674525B2 (en) * 1992-06-01 1997-01-02 Magainin Pharmaceuticals, Inc. Biologically active peptides having N-terminal substitutions

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US6348445B1 (en) 1992-06-01 2002-02-19 Magainin Pharmaceuticals, Inc. Biologically active peptides with reduced toxicity in animals and a method for preparing same
US5593866A (en) * 1992-08-21 1997-01-14 The University Of British Columbia Cationic peptides and method for production
US5847047A (en) * 1993-06-22 1998-12-08 E. I. Du Pont De Nemours And Company Antimicrobial composition of a polymer and a peptide forming amphiphilic helices of the magainin-type
FR2734492B1 (en) * 1995-05-22 1997-06-27 Rossignol Sa SNOW BOARD FEATURING A DEVICE FOR MOUNTING A BINDING OF A SHOE
US6057291A (en) 1995-06-02 2000-05-02 University Of British Columbia Antimicrobial cationic peptides
FR2735983B1 (en) 1995-06-29 1997-12-05 Centre Nat Rech Scient PEPTIDE FOR MODIFYING THE ACTIVITY OF THE HUMAN OR ANIMAL IMMUNE SYSTEM
JP3860838B2 (en) 1995-08-23 2006-12-20 ユニバーシティー オブ ブリティッシュ コロンビア Antimicrobial cationic peptide and screening method thereof
GB9818938D0 (en) 1998-08-28 1998-10-21 Alpharma As Bioactive peptides
US8283315B2 (en) 1998-08-28 2012-10-09 Lytix Biopharma As Inhibition of tumour growth
WO2001060162A2 (en) * 2000-02-15 2001-08-23 Ohio University Cationic, amphipathic beta-sheet peptides and uses thereof
DK2252627T3 (en) 2008-01-24 2017-08-14 Esperance Pharmaceuticals MERGER CONSTRUCTION WITH LYTIC DOMAIN AND METHOD FOR PRODUCING AND USING SAME.
CA2889475A1 (en) 2012-10-30 2014-05-08 Esperance Pharmaceuticals, Inc. Antibody/drug conjugates and methods of use

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CA2007913A1 (en) * 1989-01-30 1990-07-30 Michael Zasloff Composition and treatment with peptide combinations
WO1991000869A1 (en) * 1989-07-07 1991-01-24 Scripps Clinic And Research Foundation Substitution analogues of magainin peptides

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CA2111214A1 (en) 1992-12-23

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