CA2151046A1 - Treatment of septic shock with conjugated biologically active peptides - Google Patents

Treatment of septic shock with conjugated biologically active peptides

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Publication number
CA2151046A1
CA2151046A1 CA002151046A CA2151046A CA2151046A1 CA 2151046 A1 CA2151046 A1 CA 2151046A1 CA 002151046 A CA002151046 A CA 002151046A CA 2151046 A CA2151046 A CA 2151046A CA 2151046 A1 CA2151046 A1 CA 2151046A1
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Canada
Prior art keywords
amino acid
peptide
lys
hydrophilic
basic
Prior art date
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Abandoned
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CA002151046A
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French (fr)
Inventor
Mukta Hendi
Meena Rao
Taffy J. Williams
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Magainin Pharmaceuticals Inc
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Individual
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Publication of CA2151046A1 publication Critical patent/CA2151046A1/en
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    • 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
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/58—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. poly[meth]acrylate, polyacrylamide, polystyrene, polyvinylpyrrolidone, polyvinylalcohol or polystyrene sulfonic acid resin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/59—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes
    • A61K47/60—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyureas or polyurethanes the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/56—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule
    • A61K47/61—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an organic macromolecular compound, e.g. an oligomeric, polymeric or dendrimeric molecule the organic macromolecular compound being a polysaccharide or a derivative thereof
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/62—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being a protein, peptide or polyamino acid
    • A61K47/64—Drug-peptide, drug-protein or drug-polyamino acid conjugates, i.e. the modifying agent being a peptide, protein or polyamino acid which is covalently bonded or complexed to a therapeutically active agent
    • A61K47/643—Albumins, e.g. HSA, BSA, ovalbumin or a Keyhole Limpet Hemocyanin [KHL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Abstract

A compound which is a conjugate of a biologically active amphiphilic peptide and a conjugate moiety. The conjugate moiety may be a carbohydrate (such as dextran or hetastarch); a protein; polyvinyl pyrrolidone, a polyalkylene glycol; or polyvinyl alcohol. Such compounds neutralize bacterial endotoxins, and thus are particularly useful in the treatment or prevention of septic shock.

Description

W094/13697 PCT~S93/11841 TREATMENT OF SEPTIC SHOCK WIT~
CONJUGATED BIOLOGICALLY ACTIVE ~:~ll~

This invention relates to the treatment of septic shock. More particularly, this invention relates to the treatment of septic shock by administering biologically active peptides including conjugate moieties.
Septic shock is a type of shock associated with overwhelming infection. Most commonly, the infection is produced by Gram-negative bacteria (such as, for example, E.coli, Pseudomonas species, and Bacteroides species), although other bacteria, viruses, fungi, and protozoa may also be causes. The shock is believed to be caused by the action of endotoxins (such as the liposaccharide or LPS in bacterial cell walls), other products of the infectious agent, or host mediators released in response to the infectious agent or the vascular system. Such action causes altered patterns of perfusion of tissues and large volumes of blood to be sequestered in the capillaries and veins.
Bacterial endotoxin, such as LPS, at concentrations as low as a few micrograms per liter can activate immune cells in vitro. The majority of damage induced from the presence of LPS is not due to the LPS itself, but is a result of the body's complex reaction to the foreign LPS. This response TITiJ~E SHET (R~ILE 2~

W094/13697 21~ 10 4 6 -2- PCT~S93/11841 -is mediated by immune cell activation and the resultant damage that these activated cells cause to the host tissues.
Septic shock or septicemia is difficult to reverse.
Treatment following the initial signs of septic shock includes the infusion of normal saline or lactated Ringer's solution. If the shock persists, then an aggressive fluid challenge may be started, and the use of dopamine and/or norepinephrine may be recommended. More recent approaches to the treatment of septic shock are directed to the killing of bacteria and neutralizing LPS endotoxin with specific monoclonal antibodies; human bacteria permeability increasing protein (BPI); endotoxin neutralizing protein (ENP, which is obtained from the horseshoe crab); or synthetic molecules.
European Patent Application No. 428,486 discloses a conjugate of polymyxin B and a carrier, which may be employed in neutralizing bacterial endotoxins. The carrier may be a polysaccharide such as dextran or hydroxyethyl starch; a protein such as albumin; polyvinylpyrrolidone;
polyethylene glycol; or polyvinyl alcohol.
In accordance with an aspect of the present invention, there is provided a compound which is a conjugate of: (i) a biologically active amphiphilic peptide, said peptide being an ion channel-forming peptide; and (ii) a conjugate moiety selected from the group consisting of: (a) carbohydrates;
(b) proteins; (c) polyvinylpyrrolidone; (d) polyalkylene glycols; and (e) polyvinyl alcohol.
The compounds of the present invention are particularly applicable to the treatment of septic shock in that such compounds neutralize bacterial endotoxins. In general, the peptides are positively charged, while in general, the bacterial endotoxins are negatively charged. The compounds are particularly useful in that such compounds neutralize bacterial endotoxins without neutralizing essential proteins SU~S~ TE S~,E~T (R~ ILE 26) ~ 215Io~6 094/13697 ~ PCT~S93/11841 in plasma (such as heparin, for example). In addition the compounds can be constructed such that they ha~e a longer duration of activity than unconjugated peptides.
The conjugate moiety may be attached to the peptide at the C-terminal, at the N-terminal, or to an internal amino acid residue. It is to be noted, however, that the conjugate moiety should be attached to the peptide such that the peptide retains its positive charge.
In one embodiment, the conjugate moiety is a carbohydrate. Carbohydrates which may be conjugated to the peptide include, but are not limited to, dextran, hetastarch, hydroxyethyl starch, cellobiose, lactobiose, mannobiose, melibiose, lactobionic acid, and glucosamine.
In one embodiment, the carbohydrate is dextran. In another embodiment, the carbohydrate is hetastarch.
Such carbohydrates may be conjugated to the peptide at the C-terminal, the N-terminal, or to an internal amino acid. The carbohydrate may be attached through a carbamate linkage, through an amine linkage, through an ester linkage, or through bifunctional crosslinking agents.
Ester linkages o the peptide with the carbohydrate may be formed by reacting the peptide and the carbohydrate in the presence of EDCI and DMAP. The C-terminus of the peptide reacts with an -OH group of the carbohydrate to form an ester bond.
Amine linkages may be formed by oxidizing the carbohydrate with periodate to form aldehyde groups. The aldehyde is then reacted with an amino group on the peptide to form a Schiff base which then can be reduced to an amine.
If the reaction with the carbohydrate aldehyde is with hydroxylamine instead of the peptide, followed by reduction, the product is an amino-carbohydrate. The amino-carbohydrate can be reacted with a peptide to form an amide linkage.
.

SUBSTITU~E S~JEET (RU~E 26) W094/13697 21~ 4- PCT~S93/11~1 -Carbamate linkages may be formed by treating the carbohydrate with l-cyano-4-dimethyl-amino pyridinium tetrafluoroborate (CDAP), and then reacting the treated carbohydrate with a peptide having a free amino group to form a carbamate linkage.
Bifunctional crosslinking agents which may be employed for attacking the carbohydrate to the peptide include, but are not limited to, malimido groups, - S - S - O groups, and groups. Such grou~s may be attached to the carbohydrate first by attaching a -COOH group to the functional group, and then reacting the modified functional group with an -OH group of the carbohydrate to provide a carbohydrate containing the functional group. The carbohydrate with the functional group attached is then reacted with an -SH group attached to a peptide to form the conjugate.
Proteins which may be conjugated to the peptide include, but are not limited to, albumin, 2 ~
macroglobulin, antibodies or other proteins found in plasma.
The peptide may be coupled to the protein via disulfide, amide, ester, ether, or other forms of covalent bonds.
Polyvinyl pyrrolidone may be attached to the peptide through ester linkages, through carbamate linkages, or through bifunctional crosslinking agents, such as those hereinabove described.
Polyalkylene glycols which may be conjugated to the peptide include, but are not limited to, polyethylene glycol.
The polyalkylene glycol may be attached to the peptide through ester linkages, carbamate linkages, or through bifunctional crosslinking agents, whereby free -OH groups of the polyalkylene glycol are reacted to form such linkages.

SU~STITUT~ S~ET (Rl~ 26) W094/13697 2 ~ 4 6 PCT~S93/11~1 The polyvinyl alcohol also may be attached to the peptide through the linkages hereinabove described.
The biologically active amphiphilic peptides employed in the present invention are generally water-soluble to a concentration of at least 20 mg/ml at neutral pH in water.
In addition, the structure of such peptide provides for flexibility of the peptide molecule. Such peptides are capable of forming an alpha-helix. When the peptide is placed in water, it does not assume an amphiphilic structure. When the peptide encounters an oily surface or membrane, the peptide chain folds upon itself into a rod-like structure.
In general, such peptides have at least 7 amino acids.
In most cases, such peptides do not have in excess of 50 amino acids.
In general, the biologically active peptides are ion channel-forming peptides. An ion channel-forming peptide or ionophore is a peptide 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) describe methodology which indicates whether or not a peptide has ion channel-forming properties and is therefore an ionophore. As used herein, an ion channel-forming peptide is a peptide which has ion channel-forming properties as determined by the method of Christensen, et al.
An amphiphilic peptide is a peptide which includes both hydrophobic and hydrophilic peptide regions.
The compounds may be administered in an amount effective to treat or prevent septic shock in a host.
Preferably, the compounds are administered in an amount of from about 1 ~g/kg to about 5 mg/kg per host weight. The compounds may be administered to a host in vivo, such as, .

SUBSTI~UTE S~EEt (R~JL~ 26) W094/13697 2 ~ 5 10 4 ~ -6- PCT~S93/11841 -for example, through systemic administration, such as intravenous or intraperitoneal administration.
The compounds are administered in combination with an acceptable pharmaceutical carrier or vehicle such as a filler, non-toxic buffer, or physiological saline solution.
The compounds may also be used in combination with adjuvants, protease inhibitors, or compatible drugs.
In one embodiment, the peptide~is a basic (positively charged) polypeptide having at le&st sixteen amino acids wherein the polypeptide includesuàt 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 SUBSTITUTE SHEEt (RIJEE 26~

WO94/13697 21~ I 0 4 ~ PCT~S93/11~1 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, Ile, Leu, Met, Pro, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha). The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, Thr and homoserine (Hse). The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine (Har), 2, 4-diaminobutyric acid (Dbu), and p-aminophenylalanine.
Each of the groups of four amino acids may be of the sequence ABCD, BCDA, CDAB, or DABC, wherein A and B are each hydrophobic amino acids and may be the same or different, one of C or D is a basic hydrophilic amino acid, and the other of C or D is a basic or neutral hydrophilic amino acid and may be the same or different. In one embodiment, the polypeptide chain may comprise 5 or 6 groups of this sequence. In each group, each of A, B, C and D may be the same in some or all of the groups or may be different in some or all of the groups.
The polypeptide chain preferably has at least 20 amino acids, and no greater than 50 amino acids. It is to be understood, however, that the polypeptide does not have to consist entirely of the groups described above. The polypeptide may have amino acids extending from either or both ends of the noted groups forming the polypeptide chain and/or there may be amino acids between one or more of the at least four groups and still remain within the scope of the invention.
The groups of amino acids may be repeating groups of amino acids, or the amino acids in the various groups may vary provided that in each group of the at least four groups SUBSTITllTE SHEET (P~ E 26) W094/13697 21~ ~ ~ 4 ~ -8- PCT~S93/11841 -of amino acids there are two hydrophobic and two hydrophilic amino acids as hereinabove noted.
Thus the biologically active polypeptide may comprise a chain including at least four groups of amino acids, each containing four amino acids. Two of the four amino acids in each group are hydrophobic, at least one amino acid is basic hydrophilic, and the remaining onè' is basic or neutral hydrophilic, with the polypeptide chain preferably having at least 20 amino acids but no greater than 50 amino acids.
In one embodiment, each of the at least four groups of amino acids which are in the peptide chain is of the seguence 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 se~uences:
(Xl)a(A-B-C-D)n(Yl)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 Xl is D; C-D- or B-C-D-, Yl is -A or -A-B or -A-B-C
X2 is A-, D-A- or C-D-A-Y2 is -B, -B-C or B-C-D
X3is B-, A-B-, D-A-B-Y3 is -C, -C-D, -C-D-A
X4is C-, B-C-, A-B-C-Y4 is -D, -D-A, -D-A-B
a is 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 SUBSTITUT~ SH~ET (RULE ~6) ~ 4 ~
W094/13697 PCT~S93/11841 _g _ amphiphilicity and a positive charge and do not adversely affect the folding characteristics of the chain to that which is significantly different from one in which the hereinabove noted group of four amino acids are not spaced from each other.
As representative examples of such peptides, there may be mentioned.
I Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys (SEQ ID NO:l) 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-Phe-Ser-Lys-Ala- (SEQ ID NO:3) IV Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe- (SEQ ID NO:4) V Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser-Lys-Ala-Phe-Ser (SEQ ID NO:5) The peptide may have amino acids extending from either end of the chain. For example, the chains may have a Ser-Lys sequence before the "Ala" end, and/or an Ala-Phe sequence after the "Lys" end. Other amino acid sequences may also be attached to the "Ala" and/or the "Lys" end.
Similarly, in any polypeptide chain having at least four groups of amino acids of the sequence as described above, the chain may have, for example, a C-D sequence before the first A-B-C-D group. Also other amino acid sequences may be attached to the "A" and/or the "D" end of one of these polypeptide chains. Also there may be amino acids in the chain which space one or more groups of the hereinabove noted four amino acids from each other.

StJBSTITU~E SHEET (~lJLE 2~) W094/13697 2 ~ 4 ~ -lo- PCT~S93/11841 ~

In accordance with another embodiment, the peptide may be a magainin peptide.
A magainin peptide is either a magainin such as magainin I, II or III or an analogue or derivative thereof.
~he magainin peptides preferably include the following basic peptide structure Xl2~
11 11 R12 R13-Rll-R14-,R12-Rll-R14 Rl2 Rll Rll ll 14a (Rl5)n 14a 14 wherein Rll is a hydrophobic amino acid, Rl2 is a basic hydrophilic amino acid; Rl3 is a hydrophobic, neutral hydrophilic, or basic hydrophilic amino acid; Rl4 and Rl4a are hydrophobic or basic hydrophilic amino acids; Rl5 is glutamic acid or aspartic acid, or a hydrophobic or a basic hydrophilic amino acid, and n is O or l. In a preferred embodiment, Rl3 is a hydrophobic or neutral hydrophilic amino acid, Rl4a is a hydrophobic amino acid! and Rl5 is glutamic acid or aspartic acid.
Thus, for example, a magainin peptide may include the following structure:

where Xl2 is the hereinabove described basic peptide structure and Yl2 is ( i ) R12 ( ii ) R14a R12 ( iii ) Rll R14a R12 ( iv) R14-Rll-R14a-R12 Rll~ R12, Rl4 and Rl4a are as previously defined.
A magainin peptide may also have the following structure:
-Xl2-Z12-wherein Xl2 is as previously defined and Z12 is:
(i) Rl6 wher~ Rl6 is a basic hydrophilic amino acid or asparagine or glutamine.

SUBSTITUTE SI~EET (RULE ~6) ~51Q4 ~
W094/13697 PCT~S93/11841 (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:
(Y ) X12-(Z12) where X12, Y12 and Z12 are as previously defined and a is O or 1 and b is O or 1.
The magainin peptides may also include the following basic peptide structure X13:
14 11 14a 12 11 11 12 13 11 14 12 Rll Rll R12 ~ wherein Rll,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 11 n ( ll)n (Rll)n (Rl4a)n-(Rl5)n-(Rl4a)n-(Rl4) ~~
(R16) -(R17)n wherein Rll~ R14~ R14a~ R15' R16' 17 as hereinabove described, and n is O or 1, and each n may be the same or different.
The magainin peptides generally include at least fourteen amino acids and may include up to forty amino acids. A magainin peptide preferably has 22 or 23 amino acids. Accordingly, the hereinabove described basic peptide structures of a magainin peptide may include additional amino acids at the amino end or at the carboxyl end, or at both ends.
As representative examples of such magainin peptides, there may be mentioned peptides having the following primary sequences as given in the accompanying sequence listing as well as appropriate analogues and derivatives thereof:
(a) (SEQ ID NO:6) (OH) or (NH2) (Magainin I) SUBSTITUTE SHEET (RUl~

W094/13697 2 ~ 4 ~ PCT~S93/11841 -(b) (SEQ ID NO:7) (OH) or (NH2) (Magainin II) (c) (SEQ ID NO:8) (OH) or (NH2) (Magainin III) The following are examples of peptide derivatives or analogs of the basic structure:
(d) (SEQ ID NO:9) (OH) or ( ~2) (e) (SEQ ID NO:lO) (OH) or (NH2) (f) (SEQ ID NO:ll) (OH) or (NH2) Magainin peptides are described in Proc. Natl. Acad Sci . Vol . 84 pp . 5449-53 (Aug. 87). The term "magainin peptides" as used herein refers to the basic magainin structure as well as derivatives and analogs thereof, including but not limited to the representative derivatives or analogs.
In accordance with a further embodiment, the peptide may be a PGLa peptide or an XPF peptide.
A PGLa peptide is either PGLa or an analogue or derivative thereof. The PGLa peptides preferably include the following basic peptide structure Xl4:
Rll R17 Rl2 Rll 14 R14 Rll Rll 14 Rl2 ll ll 12 ll Rl 1 Rl 1 R12 where Rll, Rl2, Rl4, and Rl7 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:

where Xl4 is as previously defined and SUB~TITUTE S~ET (R~I~E 2~) W094/13697 -13- PCT~S93/11841 Y14 is (i) Rll;
(ii) R14-Rll where R11 and R14 are as previously defined.
For example, a PGLa peptide may also have the following structure:

where X14 is as previously defined; and Z14 is:
(i) Rll;
( ii ) Rll-Rll where R11 is as previously defined.
A PGLa peptide may also have the following structure:
(Y14)a 14 14 b where X14; Y14 and Z14 are as previously defined, a is O or 1 and b is O 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:
--Rll-R17-R12-Rll-R14-R18-R17-Rll-R14-R12-Rll-Rll-R12-R11 R11 Rl1 R12~(R15)n~R11~-, wherein R11, R12, R14, R15 and R17 are as previously defined and R18 is glutamine or asparagine or a basic hydrophilic, or hydrophobic amino acid and, n is O 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:

SU~TITI~TE ~HE~T (RUL~ 2~) W094/13697 2 lS 1~ ~ ~ PCT~S93/11~41 -where X16 is as previously defined and Y16 is (i) Rll or ( ii ) R14-Rll where R11 and R14 are as previously defined.
An XPF peptide may include the following structure:

where X16 is as previously defined and Z16 is (i) Rll; or (ii) Rll R18;
(iii) R11-R18-Proline; or ( iv) Rll-R18-Prline R12 An XPF peptide may also have the following structure:
(Y16)a X16 (Z16)b where X16, Y16 and Z16 are as previously defined: a is 0 or 1 and b is 0 or 1.
Preferred are XPF or PGLa peptides, which are characterized by the following primary amino acid sequences as given in the accompanying sequence Listing:
PGLa : (SEQ ID N0:12) (NH2) XPF : ( SEQ ID N0:13) A review of XPF and PGLa can be found in Hoffman et al, EMB0 J. 2:711-714, 1983; Andreu, et al, J. Biochem.
149:531-535, 1985; Gibson, et al J. Biol. Chem.
261:5341-5349, 1986; and Giovannini, et al, Biochem J.
243:113-120, 1987.
In accordance with yet another embodiment, the peptide may be a CPF peptide or appropriate analogue or derivative thereof.
CPF peptides as well as analogues and derivatives thereof are herein sometimes referred to collectively as CPF
peptides.
The CPF peptide may be one which includes the following basic peptide structure X20:

SUBSTITUT~ SHEET ~RUL~

~ 094tl3697 2151 0 ~ 6 PCT~S93/11841 wherein R2l is a hydrophobic amino acid;
R22 is a hydrophobic amino acid or a basic hydrophilic amino acid;
- R23 is a basic hydrophilic amino acid;
R24 is a hydrophobic or neutral hydrophilic amino acid;
and R25 is a basic or neutral hydrophilic amino acid.
The hereinabove basic structure is hereinafter symbolically indicated as X20.
The hydrophobic amino acids are Ala, Cys, Phe, Gly, Ile, Leu, Met, Val, Trp, Tyr, norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).
The neutral hydrophilic amino acids are ASn, Gln, Ser, Thr, and homoserine (Hse).
The basic hydrophilic amino acids are Lys, Arg, His, Orn, homoarginine (Har), 2,4-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 l to 4 additional amino acids at the amino end.
Accordingly, such preferred peptides may be represented by the structural formula:

wherein X20 is the hereinabove described basic peptide structure and Y20 is (i) R25-' or (ii) R22 R25 ; or SUBST~UTE S~IEET (RlJ~

W094/13697 21~ 6 PCT~S93/11841 (iii) R2l-R22-R25; or (iv) 22 R21 R22~R25; preferably Glycine - R21-R22 R25 wherein R2l, 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 l to 13 additional amino acids.
In a preferred embodiment, the basic structure may have from l to 7 additional amino acids at the carboxyl end, which may be represented as follows:
X20 Z20 where X is the hereinabove defined basic peptide structure and Z20 is (i) R2l-, or ( ii ) R21 R21 (iii) R2l-R2l-R24; or ( iv) R21-R21-R24 R24;
(v) 21 R21-R24-R24-R26; or (vi) R2l R2l-R24-R24-R26-Gln; or (vii) 21 R2l R24 R24~R26~Gln~Gln, wherein R2l 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 x2o (Z20)b wherein X20, Y20 and Z20 are as previously defined and a is 0 or l and b is 0 or l.
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 N0:14) (SEQ ID N0:15) S~STlT~T~ E~ UL~ 2~j * WO94/13697 2 1 51~ 4 S PCT~S93/l1~l (SEQ ID NO:16) (SEQ ID NO:17) (SEQ ID NO:18) (SEQ ID NO:l9) (SEQ ID N0:20) (SEQ ID NO:21) (SEQ ID N0:22) (SEQ ID NO:23) (SEQ ID NO:24) (SEQ ID NO:25) (SEQ ID NO:26) A review of the CPF peptides can be found in Richter, K., Egger, R., and Kreil (1986) J. Biol. Chem 261, 3676-3680;
Wakabayashi, T., Kato, H., and Tachibaba, S. (1985) Nucleic Acids Research 13, 1817-1828; Gibson, B.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 X
through X37 w X is -[R31-R32-R32-R33-R31-R32-R32]-X32 is -[R32-R32-R33-R31 R32 R32 31 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 32 33 31] n;
X i s - [ R32-R3 1-R32-R32-R33-R3 1-R32 ] -wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.
The basic hydrophilic amino acids may be selected from the class consisting of Lys, Arg, His, Orn, homoarginine TUTES~, (RUL~

W094/13697 PCT~S93/118~1 ~
2~S~0 4~ -18-(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, Ile, Leu, Met, Pro, Val, Trp and Tyr,norleucine (Nle), norvaline (Nva), and cyclohexylalanine (Cha).
The neutral hydrophilic amino acids may be selected from the class consisting of Asn, Gln, Ser, Thr, and homoserine (Hse).
In accordance with one embodiment, when the peptide includes the structure X3l, the peptide may include the following structure:
Y3l-X3l, wherein X3l is as hereinabove described, and Y3l is (i) R32;
(ii) R32-R32;
(iii) R31-R32 R32;
(iV) R33-R31-R32 R32;
(V) R32-R33-R31 R32 R32;
( ) 32 R32 R33 R3l-R32-R32~ wherein R3l, R32, and R33 are as hereinabove described In accordance with another embodiment, when the peptide includes the structure X3l, the peptide may include the following structure:
X3l-Z3l, wherein X3l is as hereinabove described, and Z31 is:
(i) R31;
(ii) R31-R32;
(iii) R31-R32 R32;
(iv) R3l-R32 R32 33 (v) R3l R32-R32-R33-R3l; or (vi) R3l-R32-R32 R33 R3l 32-In accordance with yet another embodiment, the peptidemay include the following structure:

T~ TE Si~E~ i ~RULE ~3 2151~
~ W094/13697 PCT~S93/11841 (Y31)a X31 (Z31)b~ wherein Y31 and Z31 are as previously defined, a is O or 1, and b is O or 1.
When the peptide includes the structure X32, the peptide may include the following structure:
Y32 ~ X32, wherein X32 is as hereinabove described, and Y32 is (i) R31;
(ii) R32-R31;
(iii) R32-R32 R31i (iv) R31-R32-R32 R31;
(v) 33 R31~R32~R32~R31; or (vi) R32-R33-R3l-R32 R32 31 In another embodiment, when the peptide includes the structure X32, the peptide may include the following structure:
X32 ~ Z32~ wherein X32 is as hereinabove described, and Z32 i~:
(i) R32;
(ii) R32-R32;
(iii) R32-R32-R33;
(iv) R32~R32~R33 R31;
(v) 32 R32-R33-R3l-R32; or (vi) R32-R32-R33-R31 R32 32 In accordance with yet another embodiment, the peptide may include the following structure:
( 32)a X32 (Z32)b~ wherein Y32 and Z32 are as previously defined, a is O or l, and b is O 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;

SUB~IT~E ~ E~ ~RULE26) W094/13697 21~ 10 4 ~ PCT~S93/11~1 ~

(iii) R32-R31 R32;
(iv) R32-R32-R31 R32;
(v) 31 R32-R32-R31-R32; or ) 33 31 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) 32 R33 R31-R32-R32; or (vi) R32-R33-R3l-R32 R32 31 In accordance with yet another embodiment, the peptide may include the following structure:
( 33)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) R32-R31-R32 R32;
(v) 32 R32-R31-R32-R32; or ( ) 31 R32 R32 R31~R32~R32~ wherein R31, R32 and R33 are as hereinabove described.

T~ ~E~ L~ ?~) ~ 21510~
094/13697 PCT~S93/11841 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-R3l-R32-R32 R31;
(vi) R33-R3l-R32-R32 R31 32 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 O or l, and b is O 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 33 (v) R32-R31-R32 R32 33 ( ) 32 R32 R31 R32-R32-R33~ wherein R3l, 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;

Sl~BS~IT~ T ~ULI, ~6~

W094/1369721~ 10 4 ~ -22- PCT~S93/11841 (iii) R31-R32 R32;
(iv) R3l~R32~R32 R31;
(v) 31 R32~R32-R31~R32; or (Vi ) R3l-R32-R32-R3l R32 R32 In accordance with yet another embodiment, the peptide may include the following structure: -(Y35)a X35 (Z35)b' wherein X35 and Z35 are as previously defined, a is O or 1, and b is O 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 is:
(i) R31;
(ii) R33-R31;
(iii) R32-R33 R31i (iV) R32-R32-R33 R31;
(v) 31 R32-R32-R33-R31; or ( ) 32 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;
(vi) R32-R32-R31 R32 R32 33 In accordance with yet another embodiment, the peptide may include the following structure:

BST~TUT~ L~ 'R5 IL~ ~6) ~ W094/13697 21~1 0 4 ~ PCT~S93/11841 ( 36)a X36 (Z36)b~ wherein Y36 and Z36 are as previously defined, a is O or 1, and b is O 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;
( ) 31 32;
(iii) R33-R31 R32i (iv) R32-R33-R31 R32;
(v) R32-R32-R33-R3l R32;
( ) 31 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) 32 R31~R32~R32~R33; or (vi) R32-R31 R32 R32 R33 31 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 O or 1, and b is O or 1.
In a preferred embodiment, n is 3, and most preferably the peptide is of one of the following structures as given in the accompanying sequence listing:
(Lys Ile Ala Gly Lys Ile Ala)3 (SEQ ID NO:27).
(Lys Ile Ala Lys Ile Ala Gly)3 (SEQ ID NO:28).
(Lys Ile Ala Gly Lys Ile Gly)3 (SEQ ID NO:29).

S~BSTI~UTE SHE~T (RUL~ 2~) W094/13697 PCT~S93/11841 ~
2 ~ & -24-(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 Gly)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).

SUBSTITUTE SH~ UL~ 26) ~W 2i5104~
094/13697 PCT~S93/11841 (Lys Nle Ala Lys Ile Ala Gly)3 (SEQ ID N0:64).
(Arg Ile Ala Gly Lys Ile Ala)3 (SEQ ID N0:65).
(Har Ile Ala Gly Har Ile Ala)3 (SEQ ID N0:66).
(Xaa Ile Ala Gly Lys Ile Ala)3 (SEQ ID N0:67).
(Lys Ile Ala Gly Xaa Ile Ala)3 (SEQ ID N0:68).
~ Lys Ile Ala (Lys Ile Ala Gly Lys Ile Ala)3 (SEQ ID N0:69) In (SEQ ID N0:67) and (SEQ ID N0:68), Xaa is p-aminophenylalanine.
In accordance with another embodiment, the amphiphilic peptide includes the following basic structure X40:

R -R -R -R -R34_R32-R32-R3l-R32-R32-R32-R34-R32-R32' wherein R3l, 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) R -R -R32-R32;
(v) R32 R33 R34 R32 32;
(v) R32-R32-R33-R34-R32-R32' or ( ) 31 R32 R32-R33-R34-R32-R32~wherein R3l, R32, R33 and R34 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) R3l-R32 R32 33 SUBST~TlJTE StlEET (~ULE 26) WO94/13697 21~1~ 4 6 PCT~S93/118~1 ~

(v) R31-R32-R32 R33 R34;
(vi) R -R 2-R32-R33-R34-R32; or ( ) 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 seguence listing:
(SEQ ID N0:70) In another preferred embodiment, the peptide has the following structural formula as given in the accompanying sequence listing:
(SEQ ID N0:71) In accordance with a further embodiment, the peptide has one of the one of the following structural formulae as given in the accompanying sequence listing:
(SEQ ID N0:72) (SEQ ID N0:73) (SEQ ID N0:74) (SEQ ID N0:75) (SEQ ID N0:76) (SEQ ID NO:77) (SEQ ID N0:78) (SEQ ID N0:79) (SEQ ID N0:80) (SEQ ID N0:81) (SEQ ID N0:82) (SEQ ID N0:83) (SEQ ID N0:84) (SEQ ID N0:85) (SEQ ID NO:86) SUBSTi ~ UTt ~H~L~ (R~L~ 26) 2151~4~
W094/13697 PCT~S93/11841 (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 S. 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 may be selected from the group consisting of the following structural formulae as given in the accompanying seguence listing:
(SEQ ID NO:91) (SEQ ID NO:92) (SEQ ID NO:93) (SEQ ID NO:94) In accordance with yet another embodiment, the peptide may be a cecropin or sarcotoxin.
.

2~5104~ ~
W094/13697 ^ PCT~S93/11841 The term cecropins includes the basic structure as well as analogues and derivatives thereof. The cecropins and analogues and derivatives thereof are described in Ann. Rev.
Microbiol. 1987, Vol. 41, pages 103-26, in particular page 108, and in Christensen, et al., PNAS Vol. 85, pgs. 5072-76, which are hereby incorporated by reference.
The term sarcotoxins includes the basic materials as well as analogues and derivatives thereof. The sarcotoxins and analogues and derivatives thereof are described in Molecular Entomology, pages 369-78, in particular page 375, Alan R. Liss, Inc. (1987), which is hereby incorporated by reference.
In another embodiment, the amphiphilic peptide includes the following basic structure X50:

R41 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 42 42 R41, wherein R41 and R42 are as hereinabove described.
In one embodiment, R41 is leucine. In another embodiment, R42 is lysine. Representative examples of such peptides include those having the following structures:
(SEQ ID N0: 95) (SEQ ID N0: 96) (SEQ ID N0: 97) (SEQ ID N0: 98) In accordance with another embodiment, the amphiphilic peptide includes the following basic structure X52:

SlJBST~UTE S~E~T (RULE 26) W094/13697 21~ 1 0 4 6 PCT~S93/11841 42 R41 R42 42 41 41 42 42 41 42 R42, wherein R41 is a hydrophobic amino acid and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
In one embodiment R41 is leucine. 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) 42 42 41 R41 R42.

In one embodiment, the peptide may have the following structure:
Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Arg Arg (SEQ ID NO:99) In another embodiment, the peptide includes the basic 52 Z52' wherein X52 is as hereinabove described, and Z52 is:
(i) R41;
( ii ) R41-R41;
(iii) 41 41 R42;
(iv) R41-R41-R42 R42;
(v) 41 41 42 R42 R41;

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

W094/13697%1 5 1~ 4 ~ PCT~S93/11841 -^ -30-Lys Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu 5 lO

(SEQ ID NO:lOO) In another embodiment, the peptide may include the structure:
(Y ) ~ X52 ~ (Z52)b~ wherein X52, Y52 52 hereinabove described, and a is O or l, and b is O or l.
In accordance with another embodiment, the peptide includes the following basic structure X54:

43 ' wherein R41 and R42 are as hereinabove described, and R43 is a netural hydrophilic amino acid.
In one embodiment, the peptide may have the following structure:
(SEQ ID N0:101) In another embodiment, the peptide may have the following structure:
(SEQ ID N0:102) In accordance with yet another embodiment, the peptide includes the following basic structure X56:

41 42 R41 R41 R42 R42~R41~R41~R42~R42~R44, wherein R
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:

SUBSTI~UTE S~EET (RlJ' ~ ~6) ~ WO 94/13697 2151~ ~ ~ PCT~US93/11841 ( i) -R41 (ii) -R -R
(lii) 42 41 41;
(iv) -R -R -R -R4 ;
(v) R41 R41 R42 R41 R41;
(vi) -R42-R41-R41-R42-R41-R41; or (vii) -R42-R42-R41-R41-R41 R42 R41 41' 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) -R -R
(iii) 42 42 41;
(iv) -R -R -R R
(v) R42 R42 R41- 41 R42;
(vi) -R42-R42-R41 R41-R42-R42; or (vii) 42 R42 R41- 41 42 R42 41-In a preferred embodiment, the peptide may have one of the following structures:
(SEQ ID N0:103); or (SEQ ID N0:104).

SUBSTIT~ SHE~T ~RULE ~6) W O 94/13697 PCTrUS93/11841 - ~ 32-In another embodiment, the peptide may have the ( 56)a X56-(Z56~b, wherein X56, Y56, and Z are as hereinabove described, a is O or l, and b is O or l.
In accordance with another embodiment, the peptide includes the following basic structure X58:
R -R -R42-R42-R4l-R42-R42-R4l R4l R42~ 42 41 43 wherein R4l, 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 Y58 is:

(i) -R41;
(ii) -R42-R4l;
(iii) R42 42 41;

(iv) -R4l-R42-R42 R4l;

(v) R4l R4l R42-R42 R4l;
(vi) -R42-R4l-R4l R42-R42-R4l; or (vii) 42 R42 R41_R4l R42~R42~R4l, wherein R
and R42 are as hereinabove described.
In another embodiment, the peptide includes the structure X58-Z58, wherein X58 is as hereinabove described, and Z58 is (i) -R41;
(ii) -R -R
(iil) R4l 45 45;

(iv) -R -R -R R

~l~BSTIT~ Stl~T (RJ~ E 26) W O 94/13697 2 1 ~3I O 4 ~ PCTrUS93/11841 (v) -R41-R45-R45-R43 R41;
(vi) -R41-R45-R45_R43 R41 43;
(vii) R41 R45 R45_R43 41 43 43~
(viii) 41 R45 R45-R43-R41-R43-R43-R45; or (ix) R41 R45 R45_R43 R41 R43 43 45 43~
whereln R41 and R43 are as hereinabove described, and R45 is proline.
In one embodiment, the peptide has the following structure:
(SEQ ID N0:105).
In one embodiment, the peptide may have the structure (Y58) -X5B-(Z58)b~ wherein X58, Y58' 58 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:

R -R
R -R42-R42-R42-R41~ wherein R41, R42, 43 hereinabove descrlbed. In one embodiment, the peptide may have the following structure:
(SEQ ID N0:106).
In another embodiment, the peptide may include the structure X60-Z60, wherein X60 is as hereinabove described, and Z60 is:

(i) -R42;
(ii) -R -R

SUBSTITllT~ SHE~T (RlJL~ 26) W O 94/13697 ~ PCTrUS93/11841 -_ -34-(iii) R42 R42 R41;

(iv) -R -R -R R4 ;
(v) R42 R42 R41- 41 42;
(vi) 42 R42 R41_R41~R42~R42i or .
(vii) 42 R42 R41-R41 R42 R42-R41 In accordance with yet another embodiment, the peptide has a structure selected from the group consisting of:
(a) R41-R42-R42-R41-R42-R42-R41;
(b) R41 R41 R42 R42 R41 42 42 41;
(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 N0:107), 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 N0:108), 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 SUBST~TUTE SHEET (RULE 26) ~ WO 94/13697 21~ 1 0 4 ~ PCT~US93/ll84l (SEQ ID NO:109) as given the flCC~_ L~anying sequence listing.
In yet another embodiment, the peptide has the structure (d), and a representative example of such a structure is (SEQ ID NO:llO) 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:lll) and (SEQ ID NO:112) as given in the accompanying sequence listing.
In accordance with another embodiment, the peptide has the following structural formula:
(SEQ ID NO:113).
In accordance with another embodiment, the peptide is melittin.
Melittin is an amphipsthic peptide consisting of 26 amino acid residues, and is isolated from honeybee (Apis mellifera) venom. The peptide is known to be cytolytic.
See Habermann, et al., Hoppe-Seyler's Zeitschrift Physiol. Chem., Vol. 348, pgs. 37-50 (1987). Melittin has the following structural formula as represented by the three-letter amino acid code:
Gly Ile Gly Ala Val Leu Lys Val Leu S
Thr Thr Gly Leu Pro Ala Leu Ile Ser SUBSTITIJT~ SHF~T (RULE 26~

2151~4~ --W O 94/13697 PCTnUS93/11841 Trp Ile Lys Arg Lys Arg Gln Gln (SEQ ID NO:114) In another embodiment, the peptide purified in accordance with the present inventiOn is an apidaecin.
The term apidaecin as used herein includes the basic structure as well as analogues and derivaties thereof.
Apidaecins are further described in European Patent Application No. 299,828.
In accordance with another embodiment, the peptide may be an amide - or carboxy-terminsted peptide represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide:

Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu 1eu Lys Lys Leu (SEQ ID NO:115) or the peptide may be an analogue of such peptide wherein at least one of amino acide residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from the peptide.
In one embodiment, at least one of amino acid residues 1, 3, 7, 9, 11, 12, 14, 16, or 18 is deleted from the peptide. In other embodiments, amino acid SUBSTITUT~ SHEET tF~ULE 26) 21510~

residues 1 through 3, 1 through 4, 1 through 5, 1 through 6, and 1 through 7 are deleted from the peptide.
In preferred embodiments, amino acid residues 1 through 3 or 1 through 4 are deleted from the peptide, and such peptides have the following structural formulae:
(SEQ ID NO: 116) (SEQ ID NO: 117) In accordance with another embodiment, the peptide includes the following structural formula X62:

R41 R42 R42' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid. In one embodiment, R41 is ]eucine, and in another embodiment, R4z is lysine. In a preferred embodiment, the peptide has the following structure:

Leu Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys (SEQ ID NO:118) In accordance with another embodiment, the peptide includes the following structural formula X64:

R42 R41 R41 R4z R42 41 42 42 41 41 42 42 41 41, SUBST~TUTE SH~ET (F~i~LE 26) WO 94/13697 2~ l S 1 0 4 ~ PCT/US93/11841 wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid. In one embodiment, R41 is leucine, and in another embodiment, R42 is lysine. In a preferred embodiment, the peptide has the following structural formula:

Lys Leu Leu Lys Lys l.eu Lys Lys Leu Leu Lys Lys Leu Leu (SEQ ID NO: 119) In another embodiment, the peptide includes the following structural formula X66:

41 41 42 R42 R41 42 R42 41 41 42 42 41 41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
In one embodiment, the peptide may include the following structure:
X66-Z66, wherein X66 is as hereinabove described and Z66 is:
(i) R42;
(ii) R -R ; or ( iii) R42-R41 R41 In one embodiment, R41 is leucine, and in another embodiment, R42 is lysine. In a preferred embodiment, the peptide has the following structural formula:

S~ST~TLITE S~EET (~ 2~1 w 21~1~4~
0 94/13697 PCTrUS93/11841 Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Leu Lys Leu Leu (SEQ ID N0:120) In yet another embodiment, the peptide may include the following structural formula X68:

R42-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid. In one embodiment, R41 is leucine, and in another embodiment, R42 is lysine. In a preferred embodiment, the peptide has the following structural formula:
Lys Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu (SEQ ID N0:121) The peptide may also include acetyl or octanoyl groups at the N-terminal, such groups sometimes hereinafter being indicated as Ac- and Oct-, respectlvely.
In one embodiment, each amino acid residue of the peptide is a D-amino acid residue or a glycine residue.
In another embodiment, each amino acid residue of the peptide is an L-amino acid residue or a glycine residue.

S~STITUT~ SHEET ~RlJL~ 26) WO 94/136~ PCTAUS93/11841 In yet another embodiment, the amino acid residues of the peptide which are not glycine residues may be a mixture of D-amino acid residues and L-amino acid residues.
The invention will now be described with respect to the following examples; however, the scope of the present invention is not intended to be limited thereby.
Example 1 A. Conju~ation of peptides to dextran.
The following peptldes:
(SEQ ID N0:89)-NHz;
Ac-(SEQ ID N0:99)-NH2;
Oct-(SEQ ID N0:111)-NH2;
Ac-(SEQ ID N0:116)-NH2;
Ac-(SEQ ID N0:117)-NH2;
D-(SEQ ID N0:117)-NH2, wherein each amino acid residue is a D-amino acid residue;
Ac-(SEQ ID N0:121)-NH2;
(SEQ ID N0:123)-NH2;
D-(SEQ ID N0:123)-NH2, wherein each amino acid residue is a D-amino acid residue or a glycine residue;
and Ac-(SEQ ID NO:124)-NH2 were conjugated to dextran. Such conjugation was carried out as follows:
l.Og of dextran (molecular weight 70,000-200,000) is dissolved in 50 ml of deionized water. 0.05 to 0.52g of sodium periodate is added. The reaction mixture is Sl~ST,T~IT~ S~E~T (~fUL~

WO 94/13697 215 1 ~ ~ 6 PCTrUS93/11841 stirred for 2 hours at room temperature, and then dialyzed over 4 liters of water for 4 hours using MWCO 1000. The oxidlzed dextrsn is mixed with O.3g-l.Og of peptide which is dissolved in sodium bicarbonate buffer (pH 8.0-9.0), and left in a cold room for 6 to 8 hours. The mixture was then reduced with from 3 to 30ml of 6% sodium borohydride solution for 6 to 24 hours. The reaction is then acidified with acetic acid and dialyzed for 3 to 4 days over 10 liters using MWCO and lyophilized.
B. Conju~ation of peptide to hetastarch.
Ac-(SEQ ID NO:117)-NH2 was conjugated to hetastarch as follows:
15 ml of Hespan hetastarch (molecular weight 70,000) solution was cooled in an ice bath and 50 mg of l-cyano-4-dimethylamino-pyridinium tetrafluoroborate was added, followed by 0.5ml of triethylamine solution. A
mixture of ethanol/HCl (SOm./0.5ml) was then added, and the precipitate was filtered and dissolved in 35 ml of saturated NaHC03 and water. The peptide was subsequently added as a powder to the reaction mixture and stirred at 4C overnight. It was then dialyzed over 50,000 MWCO for 4 days over 10 liters of water and lyophilized.
C. Formation of a multiple anti~enic peptide (MAP) conju~ate.

SUB~ E S~ET ~7L~ 26) 21~i104~
W O 94/13697 PCT~US93/11841 Multiple antigenic peptides are peptides built onto a brached polylysine matrix. The polylysine matrix is comprised of 7 lysine residues built on a solld phase resin with a B-alanine spacer~ Multiple antigenic peptides serve as a model for peptide-protein conjugates.
The synthesis of the multiple antigenic peptide conjugate is carried out using solid phase methodology on an ABI-431 peptide synthesizer. (SEQ ID NO:lZZ) is built on the matrix such that eight copies of (SEQ ID NO:12Z) are attached to the matrix. The cleavage and purification of the MAP peptides are carried out using standard methodology.
Example Z
Thirteen groups of CD-1 mice, with each group having 10 mice, were given actinomycin D in order to sensitize the mice to endotoxin. Each mouse ws injected with 20 micrograms of endotoxin. A control group of mice received an intraperitoneal challenge of from 0.lmg to l.Omg of Endotoxin 0lll:B4. The other groups of mice received an intraperitoneal challenge of from O.lmg to l.Omg of Endotoxin 0lll:B4 and from O.lmg to 7mg of one of the peptide conjugates described in Example 1. The conjugates had a peptide/polymer ratio of from 3% to 25%
wt./wt. The con~ugates were premixed with the endotoxin for 30 minutes prior to the intraperitoneal challenge.
Survivors were assessed on a daily basis for 7 days. The SUBSTITl~TE SHEE ~ 3LE ~) 21~1Q~
W O 94/13697 PCT~US93/11841 ratio of the number of survivors in each of the conjugate treatment groups at Day 2 and Day 7 to the number of survivors in the control groups is given in Table below.

Table 1 Conju~ate Survivor Ratio Day 2 Day 7 (SEQ ID NO: 89 ) -NH2-dextran 3.3 9 Ac-(SEQ ID NO: 99)-NH2-dextran 3.3 8 Oct-(SEQ ID NO:lll)-NH2-dextran 10 10 Ac-(SEQ ID NO:116)-NH2-dextran 4.5 4 Ac-(SEQ ID NO:117)-N~2-dextran 5 8 D-(SEQ ID NO:117)-NH2-dextran 9 8 Ac-(SEQ ID NO: 117)-NH2-hetastarch2.5 Ac-(SEQ ID NO:121)-NH2-dextran 3.3 9 (SEQ ID NO:122)-MAP 3.5 2 (SEQ ID NO:123)-NH2-dextran 3.5 5 D-(SEQ ID NO:123)-NH2-dextran 4 3 Oct-(SEQ ID NO:124)-NH2-dextran 3.3 9 It is to be understood, however, that the scope of the present invention is not to be limited to the specific embodiments described above. The invention may be practiced other thsn as particularly described and still be within the scope of the accompanying claims.

~;UB~T~TUTE SHEET (Ri~LE 26) W094/13697 %~5 ~ PCT~S93/11841 -~U~CE LISTING

(l) GENERAL INFORMATION:
(i) APPLICANT: Williams, Ta~fy J.
Hendi, Mukta Rao, Meena (ii) TITLE OF INVENTION: Treatment of Septic Shock with Conjugated Biologically Active Peptides (iii) NUMBER OF SEQUENCES:

(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) COM~l~K 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: 07/987,443 (B) FILING DATE: 07-DEC-1992 (C) CLASSIFICATION:

SllBSTITUT~ SHE~T ~RULE 26) 21~10~g WO94/13697 PCT~S93/11841 (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: 421250-220 (ix) TELECOMMUNICATION INFORMATION:
(A) TELEPHONE: 201-994-1700 (B) TELEFAX: 201-994-1744 (2) INFORMATION FOR SEQ ID NO:l:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 20 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (x) PUBLICATION INFORMATION:
(H) DOCUMENT NUMBER: W089/11290 (I) FILING DATE: l9-MAY-1989 (J) PUBLICATION DATE: 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:l:
Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys (2) INFORMATION FOR SEQ ID NO:2:

SUB~ITUTE ~HE~T (RULE 26~

W094/13697 PCT~S93/11841 (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: l9-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 Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys 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: l9-MAY-1989 (J) PUBLICATION DATE: 30-NOV-1989 ~UBSTITU~ SE ~ET (~L~ 2~) 2I~10~
W094/13697 PCT~S93/11~1 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:
Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala (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: l9-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 Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe (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 ~UBST~T~JT~ SHEET (Rl~l~E 26) W094/13697 2151~ ~ ~ PCT~S93/118~1 ~

(x) PUBLICATION INFORMATION:
(H) DOCUMENT NUMBER: W089/11290 (I) FILING DATE: l9-MAY-1989 (J) PUBLICATION DATE: 30-NOV-1989 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:
Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser Lys Ala Phe Ser (2) INFORMATION FOR SEQ ID NO:6:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH 23 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: Magainin I peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Zasloff, Michael (C) JOURNAL: Proc. Nat. Acad. Sci.
(D) VOLUME: 84 (F) PAGES: 5449-5453 (G) DATE: AUG - 1987 (H) DOCUMENT NUMBER: US 4810777 (I) FILING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 S~ ITU~ SH~ET (R~ll E 2~) 21S10~
W094/13697 PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:
Gly Ile Gly Lys Phe Leu His Ser Ala Gly Lys Phe Gly Lys Ala Phe Val Gly Glu Ile 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 W094/13697 21510 4~ PCT~S93/11841 -(xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:
Gly Ile Gly Lys Phe Leu His Ser Ala Lys 5 lO
Lys Phe Gly Lys Ala Phe Val Gly Glu Ile 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 48lO777 (I) FILING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 SUBSTlTlJT~ SH~ET (RULE 26) ~ 2~51~4~
094/13697 - PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:
Gly Ile Gly Lys Phe Leu His Ser Ala Lys 5 lO
Lys Phe Gly Lys Ala Phe Val Gly Glu Ile 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 48lO777 (I) FILING DATE: 04-MAR-1987 (J) PUBLICATION DATE: 07-MAR-1989 SUBSTITUTE SHEET (RULE 26~

W094/13697 PCT~S93/11841 -21~ ~ 4~ -52-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:
Ile Gly Lys Phe Leu His Ser Ala Lys Lys Phe Gly Lys Ala Phe Val Gly Glu Ile Met 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 SUBSTITUTE SHEET (RUL~ 26~

21~
WO94/13697 PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:
Gly Lys Phe Leu His Ser Ala Lys Lys Phe - Gly Lys Ala Phe Val Gly Glu Ile Met Asn Ser (2) INEORMATION FOR SEQ ID NO:ll:
(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:ll:
Lys Phe Leu His Ser Ala Lys Lys Phe Gly Lys Ala Phe Val Gly Glu Ile Met Asn Ser SUBSTITIJTE SHEET (RULE 26) W094/1369~l 5 ~ 54- PCT~S93/11841 -(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 (~) 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 SUBSTITUT~ SHEET (R~LE 26) ~WO 94/13697 21 51 0 4 ~ PCT/US93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:
Gly Met Ala Ser Lys Ala Gly Ala Ile Ala Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INEORMATION FOR SEQ ID NO:13:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 25 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: XPF peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Hoffman, et al.l (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 SllBSTITUTE SH~ET (RULE 26`.

: ~ =

W094/13697 PCT~S93111841 ~
2 ~ 5 ~ 56-(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 Gly Lys Ile Ala Lys Val Gly Leu Lys Glu Leu Ile Gln Pro Lys ~5 (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: CPE peptide.

(x) PUBLICATION INFORMATION:
(A) AUTHOR: Richter, K.
Egger, R.
Kreil (C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 26l (F) PAGES: 3676-3680 SUBSTITUTE SHEET (RULE 26) ~ 094/13697 21510 ~ ~ PCT~S93/11841 (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: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:
Gly Phe Gly Ser Phe Leu Gly Leu Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ala Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:15:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear SUB~TITUTE S! IEET (RULE 25`~

W094/13697 PCT~S93/11841 ~l5l~4~
(ii~ MOLECULE TYPE: peptide (ix) FEATURE:
(A) NAME/KEY: CPF peptide.

(x) PUBLICATION INFORMATIQN:
(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: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

SUBST~TUTE SHEET ~RUL~ 26) WO94/13697 2151 0 ~ fi PCT~S93/1l~1 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:
Gly Leu Ala Ser Phe Leu Gly Lys Ala Leu Lys Ala Gly Leu Lys Ile Gly Ala His Leu - Leu Gly Gly Ala Pro Gln Gln (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 SUBSTlTUTE SHE~T (RULE 26) WO94/13697 PCT~S93/11841 -(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: WO90/04407 (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 Lys Ala Gly Leu Lys Ile Gly Thr His Phe Leu Gly Gly Ala Pro Gln Gln (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:

SUBSTITUTE SHEET (RULE 26) ~I510~ ~
094/13697 PCT~S93/11841 (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: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:
Gly Leu Ala Ser Leu Leu Gly Lys Ala Leu Lys Ala Thr Leu Lys Ile Gly Thr His Phe Leu Gly Gly Ala Pro Gln Gln SUBSTITUT~ SHEET (RVLE 26) W094/13697 215 l ~ 4 ~ -62- PCT~S93/11841 -(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 SU~TI~U~ SHi-~T (RULE 26) ~ 21510~
WO94/13697 PCT~S93/11841 (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 Lys Ala Ala Leu Lys Ile Gly Ala Asn Met Leu Gly Gly Thr Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:l9:
(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.

SUBSTITUT~ SHEET (RULE 26) W094/l3697 2 1~ la ~ -64- PCT~S93/11~1 -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: WO90/04407 (I) EILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:l9:
Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ala Pro Gln Gln (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 SL1BSTITIJTE SHEET (RllLE 26) W094/13697 ~ PCT~S93/11841 (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: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

SUBSTITUTE SHEE~ (RUL~ 26) W094/13697 2~S~Q 46 PCT~S93/11841 -(xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:
Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ser Pro Gln Gln (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 SUBSTITUTE SHEEt ~RULE 26) w 21510~$
094/13697 ^ PCT~S93/11841 (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: WO90/04407 (I) FILING DATE: 16-OCT-1989 (J) PUBLICATION DATE: 03-MAY-l99O

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:
Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Leu Leu Gly Gly Thr Pro Gln Gln (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:

SUBSTITU~E SHEFT ~RU~E 26) W094/13697 PCT~S93/11841 -~S~-~ 4~ -68-(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 Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ala Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:23:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids iT~lTE SHE~ (RULE ~6) 2151Q~
WO94/13697 ^ PCT~S93/11~1 (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 SUBSTITUTE SHEET (RU~

WO 94/13697 PCTtUS93/l1841 ~S~ 4~
- (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:
Gly Phe Ala Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Met Leu Gly Gly Ala Pro Gln Gln (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 SU~STITUT~ SH ~ i ~RUL~ ~6) WO94/13697 21510 4 ~ PCT~S93/11841 (G) DATE: 1985 (A) AUTHOR: Gibson, B.W.
Poulter, L.
Williams, D.H.
Maggio, J.E.
(C) JOURNAL: J. Biol. Chem.
(D) VOLUME: 26l (F) PAGES: 5341-5349 (G) DATE: 1986 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:
Gly Phe Gly Ser Phe Leu Gly Lys Ala Leu Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ser Leu Gln Gln (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 SUBSTITUTE SHEET (RULE 26) W094/13697 PCT~S93/11841 ~
2i5 ~ ~ -72-(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 Lys Ala Gly Leu Lys Ile Gly Thr Asn Phe Leu Gly Gly Ala Pro Gln Gln (2) INFORMATION FOR SEQ ID NO:26:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 27 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:

SUBSTIME SHEET (RULE 26) ~ 2~1Q4~
W094/13697 I PCT~S93111841 (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 SlJBSTlTUTE S~IEET (RULE 26) PCT~S93/11841 Lys Ala Ala Leu Lys Ile Gly Ala Asn Ala Leu Gly Gly Ser Pro Gln Gln (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 Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile 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 SUBSTlTiJTE SH~ET (RlJLE 26) WO94/13697 _75 PCT~S~ill~l Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala 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 Gly Lys Ile Gly Lys Ile Ala Gly Lys Ile 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 SU~STITUTE SHEE ~ (RIJLE 26) ~\~ 10Ll(o W094/13697 PCT~S93/11841 Gly Lys ~u Ala Lys Leu Ala Gly Lys Leu Ala (2) INFORMATION FOR SEQ ID NO:3l:
(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:3l:
Lys Phe Ala Gly Lys Phe Ala Lys Phe Ala 5 lO
Gly Lys Phe Ala Lys Phe Ala Gly Lys Phe Ala (2) INFORMATION FOR SEQ ID NO:32:

(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l 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 lO

T~Tl)TE SHEET (RULE 26) WO94/13697 21~ 1 0 4 ~ ~CT~S93/11841 Ser Lys Ala Leu Lys Ala Leu Ser Lys Ala 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 l0 Lys Ala Leu Gly Lys Leu Leu Lys Ala Leu 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 l0 SUBSTI~UTE SHEET (R~L~ 26) WO94/13697 PCT~S93/11841 2~S ~ 78-Gly Lys Ala Ile Lys Ala Ile Gly Lys Ala 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 Lys Ile Ala Lys Gly Ile Ala Lys Ile Ala 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 SUBSTIT~JT~ SH~ET (RU~ 26) W094/13697 215 10 4 6 PCT~S93/11841 Lys Ile Phe Gly Lys Ile Ala Lys Ile Phe Gly (2) INFORMATION FOR SEQ ID NO:37:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l 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 lO
Arg Ile Ala Lys Gly Ile Ala Arg Ile Ala l5 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 lO

SlJBSTlTUTE SHEE~ (RULE 2~) W094/13697 PCT~S93/11841 -2i5 lQ 4~ -80-Arg Ile Ala Gly Lys Phe Ala Arg Ile Ala 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 lO
Lys Ile Ala Lys Gly Phe Ala Lys Ile Ala Lys (2) INFORMATION FOR SEQ ID NO:40:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is ornithine (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:
Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala 5 lO

Sl3BSTIrUTE SHEET (RUL~ 26) WO94/13697 ~CT~S93/11841 Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile 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 Arg Ile Ala Gly Lys Ile Ala Arg Ile Ala 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 S~STITllTE SHE~T (Rl~LC 2~) W094/13697 PCT~S93/11841 -2l 5 ~ 4~ -82-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:
Xaa Ile Ala Gly Lys Ile Ala Xaa Ile Ala 5 lO
Gly Lys Ile Ala Xaa Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:43:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l 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 lO
Arg Ile Phe Lys Gly Ile Ala Arg Ile Phe 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.

SU~TI~UTE SHE~T (~L~ 2~) ~151~46 WO94/13697 PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:
Lys Xaa Ala Gly Lys Xaa Ala Lys Xaa Ala 5 l0 Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa 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 l0 Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ile 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 S~B~TITUT~ SHEET (RU~E 26) W094/13697 2 ~ PCT~S93111841 (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 Gly Lys Xaa Ala Lys Ile Ala Gly Lys Xaa Ala (2) INFORMATION FOR SEQ ID NO:47:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l 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 Gly Lys Xaa Ala Lys Xaa Ala Gly Lys Xaa Ala (2) INFORMATION FOR SEQ ID NO:48:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:

iTUT~ S~E~, (Rl tL~ 26) ~104~
WO94/13697 PCT~S93111841 (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 Gly Lys Ile Ala Lys Xaa Ala Gly Lys Xaa 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 Ser Lys Leu Gly Lys Leu Leu Ser Lys Leu Gly (2) INFORMATION FOR SEQ ID NO:50:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid SUBSTtTU~ S~E~T (RULE 26) W094/13697 21~ 10 ~ ~ PCT~S93/11841 (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 lO
Ser Lys Phe Gly Lys Leu Leu Ser L~s P~e 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) OTEER INFORMATION: Xaa is norvaline.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:
Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala 5 lO
Gly Lys Xaa Ala Lys Ile Ala Gly Lys Xaa Ala (2) INFORMATION FOR SEQ ID NO:52:
(i) SEQUENCE CEARACTERISTICS
(A) LENGTH: 2l amino acids SUBSTITUTE S~lEET (RULE 26) ~ W094/13697 2 ~ ~1 0 ~ 6 PCT~S93/11841 (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 Gly His Ile Ala His Ile Ala Gly His Ile 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 Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile (2) INFORMATION FOR SEQ ID NO:54:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:

SUBSTITUTE Sl lEET (RULE 26 -WO94/13697 2~ 4~ -88- PCT~S93/11841 -(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:
Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly 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 Gly Arg Ile Ala Lys Ile Ala Gly Arg Ile 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 SUBSTI~UTE SHEET (RULE 26~

WO94/13697 2151 Q 4 ~ PCT~S93/11841 (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:
Arg Ile Ala Gly Arg Ile Ala Arg Ile Ala 5 lO
Gly Arg Ile Ala Arg Ile Ala Gly Arg Ile 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 l0 Gly Lys Ile Ala Lys Val Ala Gly Lys Ile 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 S~J~STITI ITE SltEET (RlJL~ 26) WO94/13697 PCT~S93/11841 -215~ go-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:
Lys Ile Ala Gly Lys Val Ala Lys Ile Ala Gly Lys Val Ala Lys Ile Ala Gly Lys Val Ala (2) INFORMATION FOR SEQ ID NO:59:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l 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 Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys 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.

SUBSTITU~E SHEET (RIJ~E 26) ~ 094/13697 2151 ~ 4 6 PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:
Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile 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 Gly Lys Ile Ala Lys Phe Ala Gly Lys Ile 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 ~U~S~iTLlTE SHEET (RULE 26~

WO94/1307 215 10 ~ ~ -92- PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:
Lys Ile Ala Gly Lys Phe Ala Lys Ile Ala Gly Lys Phe Ala Lys Ile Ala Gly Lys Phe 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 Gly Lys Ile Ala Lys Xaa Ala Gly Lys Ile 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: pept~de ~IJBS ~ ITUTE SH~ET (RUI E 26) 2 1 ~
~ WO94/13697 - PCT~S93/11841 (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine.

t (Xi ) SEQUENCE DESCRIPTION: SEQ ID NO:64:
Lys Xaa Ala Lys Ile Ala Gly Lys Xaa Ala 5 l0 Lys Ile Ala Gly Lys Xaa Ala Lys Ile Ala 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 l0 Gly Lys Ile Ala Arg Ile Ala Gly Lys Ile 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 SUBSTITUTE SHEET (RULE 2~) WO94/13697 2 i ~ ~ ~ 4 ~ -94- PCT~S93111841 ~

(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 Gly Xaa Ile Ala Xaa Ile Ala Gly Xaa Ile 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 Gly Lys Ile Ala Xaa Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:68:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear ~BSTi~TE ~EET (Rl)LE 26) WO94/13697 21~10 ~ ~ ~ PCT~S93/11841 (ii) MOLECULE 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 Gly Xaa Ile Ala Lys Ile Ala Gly Xaa Ile 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 Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:70:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear SUBSTITUTE SHEET (RULE 26) W094/13697 ~ 4 PCT~S93/11841 -(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:
Lys Leu Ala Ser Lys Ala Gly Lys Ile Ala Gly 5 lO
Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:71:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l 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 lO
Xaa Ile Ala Lys Ile Ala Gly Lys Ile Ala (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 SUBSTITUTE SHEET (RULE 26~

WO94/13697 2~ 51~ ~ ~ PCT~S93/11~1 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Arg Ile Ala Lys Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:73:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFORMATION: Xaa is norleucine.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile 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 ~UBSTITUTE SHEET (RULE 26) W094/13697 ~ 4 ~ PCT~S93/11841 (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 Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile 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 Xaa Phe Ala Lys Phe Ala Gly Lys Phe Ala (2) INFORMATION FOR SEQ ID NO:76:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear Sl~BSTl~l) i E SHEET (RULE 26~

~ 2 1 ~
W094/13697 PCT~S93/11841 _99_ (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 Gly Xaa Phe Ala Lys Ile Ala Gly Lys Phe 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 Gly Xaa Xaa Ala Lys Ile Ala Gly Lys Xaa Ala (2) INFORMATION FOR SEQ ID NO:78:

SUBSTITUTE SHEET (P~U~ 26) W094/13697 PCT~S93/11841 ~
2~ 51~ 4~ -loo-(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 lO
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala 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 lO
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:80:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l amino acids (B) TYPE: amino acid SUBSTITUTE SHEET (P~ULE ~6'J

~ WO94/13697 ~151~ 4 ~ PCT~S93111841 (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 Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (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 Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:82:

SUBSTITUTE SHEET (RULE 26~

2 ~ -102- PCT~S93/11841 (i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 2l 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 .
Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (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.

~BST~T~TE S~IEET (RULE 26) ~ 104fi WO94/13697 PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala 5 l0 Gly Xaa Ile Ala Lys Ile Ala Gly Lys Ile 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 l0 Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile 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 SUBSTITUTE SHEET (RULE 26~

W094/13697 PCT~S93/11841 2 ~ 4 ~ -104-(xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:
Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala 5 lO
Gly Ala Ile Ala Lys Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:86:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 2l 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 lO
Gly Lys Ile Ala Lys Ile Ala Gly Ala Ile 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 SUB~T~, UTE ~H~ET (RI~LE 26) ~ 2151~4~
094/13697 ~ PCT~S93/11841 5 l0 Ala Lys Ile Ala Lys Val Ala Leu Lys Ala l0 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 l0 Lys Lys Ile Ala Lys Ile Ala Lys Lys Ile 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 l0 Lys Lys Phe Ala Lys Phe Ala Lys Lys Phe SUBSTltUT~ SHEET (RULE ~6~

W094/13697 1~ ~Q ~ -106- PCT~S93/118~1 -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 Lys Lys Ile Ala Lys Phe Ala Lys Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:9l:
(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:9l:
Ala Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile Ala ~l~BST~T~TE S~E~T (RUL~ 2~) WO94/13697 21~ 10 4 ~ PCT~S93/11841 (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 Gly Lys Ile Ala Lys Ile Ala Gly Lys Ile 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 Gly Lys Ile Ala Ala Ile Ala Gly Lys Ile Ala (2) INFORMATION FOR SEQ ID NO:94:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 21 amino acids (B) TYPE: amino acid SUBSTITUTE SHEET (RULE 26~

W094/13697 PCT~S93/11841 215 1 Q ~6 (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 Gly Lys Ile Ala Lys Val Ala Leu Lys Ala Leu (2) INFORMATION FOR SEQ ID NO:95:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: ll 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 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 SUBSTITUTE SHEET (RLJL~ 2~) ~A~ 21510~
094/13697 PCT~S93/11841 - 109 - I ~

(xi) SEQUENCE DESCRIPTION:SEQ ID NO:96:
Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys 5 lO
~ 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 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 Leu Lys Leu Leu SUB~ITI IT~ SHEET (~'L3LE 26) W094tl3697 PCT~S93/11841 -2 ~ 4~ -110-(2) INFORMATION FOR SEQ ID NO:99:
(i) SEQUENCE CHARACTERISTICS:
(A) LE~GTH: 16 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) SEQUENCE DESCRIPTION: SEQ ID NO:99:
Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Arg Arg (2) INFORMATION FOR SEQ ID NO:lOO:
(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:lOO:

Lys Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Leu Leu (2) INFORMATION FOR SEQ ID NO:lOl:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:

S~B~TlTlJT~ SHEET (RUEE 26) 2 1 ~
~ 094/13697 PCT~S93/11841 (D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:lOl:
Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Asn (2) INFORMATION FOR SEQ ID NO:102:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLQGY: 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 Leu Leu Lys Lys Xaa (2) INFORMATION FOR SEQ ID NO:103:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear .

SUBSTITUTE SHEET`(RULE 26~

W094113697 ~ ~ Q 4 6 -112- PCT~S93/11841 -(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:
Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Asn Lys Lys Leu Leu Lys Lys Leu (2) INFORMATION FOR SEQ ID NO:lO4:
(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 Pro Lys Lys Leu Leu Lys Lys Leu (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:

SIJBSTITUTE SltFET (RULE 26) 21 ~1~4~
W094/13697 PCT~S93/11841 -l13-Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys 5 lO
Lys Leu Gln Gly Pro Pro Gln Gly Gln Ser 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 lO
Lys Ile Ala Lys Lys Leu Leu Lys Lys Leu (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 Sl~BST~TUTE SH~ET (~ULE-26) W094/136972 ~ 5 1~ ~ ~ PCT~S93/11841 (2) INFORMATION FOR SEQ ID NO:108:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 8 amino acids (B) TYPE: amino acid (C) STRANDEDNESS: -1.
(D) TOPOLOGY: linear .

(ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:
Leu Leu Lys Lys Leu Lys Lys Leu (2) INFORMATION FOR SEQ ID NO:lO9:
(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 (2) INFORMATION FOR SEQ ID NO:llO:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 10 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide SUBSTITUTE SHEET (RULE 2~) ~ 21510~fi W094/13697 ~ PCT~S93/11841 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:llO:
Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu 5 lO
-(2) INFORMATION FOR SEQ ID NO:lll:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: ll amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:lll:
Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu 5 lO

(2) INFORMATION FOR SEQ ID NO:112:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: ll 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 lO

(2) INFORMATION FOR SEQ ID NO:113:
(i) SEQUENCE CHARACTERISTICS
(A) LENGTH: 14 amino acids (B) TYPE: amino acid SUBSTITIJTE SHEET (RULE 2B) W094/13697 215 la ~ -116- PCT~S93111841 -(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 Leu Lys Arg (2) INFORMATION FOR SEQ ID NO:114:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 26 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (vi) ORIGINAL SOURCE
(A) ORGANISM: Apis mellifera (vii) FEATURE

(A) NAME/KEY: melittin peptide (x) PUBLICATION INFORMATION:
(A) AUTHORS: Habermann, E.
Jentsch, J.
(B) TITLE: Sequenzanalyse des Melittins aus den tryptischen and peptischen Spaltstucken (C) JOURNAL: Hoppe-Seyler's Zeitschrift Physiol. Chem.

SliBS ~ ITUTE SH~ET (~ULE 26) ~w 21S104~
094/13697 PCT~S93111841 (D) VOLUME: 348 (F) PAGES: 37-50 (G) DATE: 1987 (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:
Gly Ile Gly Ala Val Leu Lys Val Leu Thr Thr Gly Leu Pro Ala Leu Ile Ser Trp Ile Lys Arg Lys Arg Gln Gln (2) INFORMATION FOR SEQ ID NO:115:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 18 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:
Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu (2) INFORMATION FOR SEQ ID NO:116:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 15 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear SUBSTlTUtE,SHEET (RULE ~6) W094/13697 ~ 4~ -118- PCT~S93/11841 (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFORMATION: C-terminal amide, may be acetylated at N-terminus.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:
Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu (2) INFORMATION FOR SEQ ID NO:117:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (ix) FEATURE:
(D) OTHER INFORMATION: C-terminal amide, may be acetylated at N-terminus.

(xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:
Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu (2) INFORMATION FOR SEQ ID NO:118:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 14 amino acids (B) TYPE: amino acid ~tJBSTIME StlEET (RULE 26~

W094/13697 2 ~ ~ 1 n ~ ~ PCT~S93/11841 (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:
Leu Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys (2) INFORMATION FOR SEQ ID NO:ll9:
(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:ll9:
Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu Leu (2) INFORMATION FOR SEQ ID NO:120:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 16 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:

SUBSTITUTE SHEET (RULE 26) ~5 l~
WO94/13697 PCT~S93/11841 Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys 5 l0 Lys Leu Leu Lys Leu Leu (2) INFORMATION FOR SEQ ID NO:12l:
(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:121:
Lys Lys Leu Leu Lys Lys Leu Leu Lys Lys 5 lO
Leu Leu Lys Lys Leu (2) INFORMATION FOR SEQ ID NO:122:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 22 amino acids (B) TYPE: amino acid (C) STRANDEDNESS:
(D) TOPOLOGY: linear (ii) MOLECULE TYPE: peptide (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:
Gly Ile Gly Lys Phe Leu Lys Lys Ala Lys Lys 5 lO
Phe Gly Lys Ala Phe Val Lys Ile Leu Lys Lys SUBSTIT~$E SHEET (RtilE 26) WO94/13697 _ ~1 5 I O 1 ~ PCT~S93/11841 (2) INFORMATION FOR SEQ ID NO:123:
(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:123:
Gly Ile Gly Lys Phe Leu Lys Lys Ala Lys Lys Phe Ala Lys Ala Phe Val Lys Ile Ile Asn Asn (2) INFORMATION FOR SEQ ID NO:124:
(i) SEQUENCE CHARACTERISTICS:
(A) LENGTH: 11 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:124:
Leu Xaa Xaa Leu Leu Xaa Xaa Leu Xaa Xaa Leu SUBSTITUTE SHEET (RUEE 26)

Claims (68)

WHAT IS CLAIMED IS:
1. A compound, said compound being a conjugate of: (i) a biologically active amphiphilic peptide, said peptide being an ion channel-forming peptide, and said peptide being capable of forming an -helix; and (ii) a conjugate moiety selected from the group consisting of: (a) carbohydrates; (b) proteins; (c) polyvinyl pyrrolidone; (d) polyalkylene glycols; and (e) polyvinyl alcohol.
2. The compound of Claim 1 wherein said conjugate moiety is a carbohydrate.
3. The compound of Claim 2 wherein said carbohydrate is selected from the group consisting of dextran, hetastarch, hydroxyethyl starch, cellobiose, lactobiose, mannobiose, melibiose, lactobionic acid, and glucosamine.
4. The compound of Claim 3 wherein said carbohydrate is dextran.
5. The compound of Claim 3 wherein said carbohydrate is hetastarch.
6. The compound of Claim 1 wherein said conjugate moiety is a protein.
7. The compound of Claim 1 wherein said protein is selected from the group consisting of albumin and 2-macroglobulin.
8. The compound of Claim 1 wherein said conjugate moiety is polyvinyl pyrrolidone.
9. The compound of Claim 1 wherein said conjugate moiety is a polyalkylene glycol.
10. The compound of Claim 1 wherein said polyalkylene glycol is polyethylene glycol.
11. The compound of Claim 1 wherein said conjugate moiety is polyvinyl alcohol.
12. The compound of Claim 1 wherein said peptide is selected from the group consisting of:
(a) magainin peptides;
(b) PGLa peptides;

(c) XPF peptides;
(d) CPF peptides;
(e) cecropins;
(f) sarcotoxins;
(g) a peptide including one of the following basic structures X31 through X37, wherein:
X31 is -[R31-R32-R32-R33-R31-R32-R32]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-;
X37 is -[R32-R31-R32-R32-R33-R31-R32]n-;
wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5;
(h) a peptide including the following basic structure X40:
R31-R32-R32-R33-R33-R32-R32-R31-R32-R32-R32-R34-R32-R32, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid;
(i) a peptide including the following basic structure X50:
R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41-, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophobic amino acid;
(j) a peptide including the following basic structure X52:
R42-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid;
(k) a peptide including the following basic structure X54:

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;
(1) a peptide including the following basic structure X56:
R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline;
(m) a peptide including the following basic structure X58:
-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R43, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid;
(n) a peptide including the following basic structure X60:

R42-R42-R41-R41-R42-R42-R42-R41, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid;
(o) a peptide having a structure selected from the group consisting of:
(i) R41-R42-R42-R41-R42-R42-R41;
(ii) R41-R41-R42-R42-R41-R42-R42-R41;
(iii) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(iv) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and (v) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic amino acid or a neutral hydrophilic amino acid;
(p) a peptide, being in an amide- or carboxy-terminated form, said peptide being represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide:
LeuLysLeuLeuLysLysLeuLeuLysLysLeuLysLysLeuLeuLysLysLeu or an analogue of said peptide wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from said peptide;
(q) a peptide including the following structural formula X62:

wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid;
(r) a peptide including the following structural formula X64:
R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41' wherein R41 is a hydrophobic amino acid and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
(s) a peptide including the following structural formula X66:
R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
(t) a peptide including the following structural formula X68:

-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid;
(u) melittin; and (v) apidaecins.
13. The compound of Claim 12 wherein the peptide is a magainin peptide.
14. The compound of Claim 12 wherein the peptide is a PGLa peptide.
15. The compound of Claim 12 wherein the peptide is an XPF
peptide.
16. The compound of Claim 12 wherein the peptide is a CPF
peptide.
17. The compound of Claim 12 wherein the peptide is a cecropin.
18. The compound of Claim 12 wherein the peptide is a sarcotoxin.
19. The compound of Claim 12 wherein the peptide 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, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.
20. The compound of Claim 12 wherein the peptide includes the following basic structure X40:
R31-R32-R32-R33-R34-R32-R32-R31-R32-R32-R32-R34-R32-R32, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid.
21. The compound of Claim 12 wherein said peptide includes the following basic structure X50:
R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
22. The compound of Claim 12 wherein said peptide includes the following basic structure X52:
R42-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
23. The compound of Claim 12 wherein the peptide includes the following basic structure X54:
-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R43-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
24. The compound of Claim 12 wherein the peptide includes the following basic structure X56:
R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline.
25. The compound of Claim 12 wherein the peptide includes the following basic structure X58:
-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R43-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
26. The compound of Claim 12 wherein the peptide includes the following basic structure X60:

-R41-R42-R42-R42-R41-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
27. The compound of Claim 12 wherein the peptide has a structure selected from the group consisting of:
(i) R41-R42-R42-R41-R42-R42-R41;
(ii) R41-R41-R42-R42-R41-R42-R42-R41;
(iii) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(iv) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and (v) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic amino acid or a neutral hydrophilic amino acid.
28. The compound of Claim 12 wherein said peptide is a peptide being in an amide- or carboxy-terminated form, said peptide being represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide:
Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu or an analogue of said peptide wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from said peptide.
29. The compound of Claim 12 wherein said peptide includes the following structural formula X62:
R41-R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
30. The compound of Claim 12 wherein said peptide includes the following structural formula X64:
R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41' wherein R41 is a hydrophobic amino acid and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
31. The compound of Claim 12 wherein said peptide includes the following structural formula X66:
R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
32. The compound of Claim 12 wherein said peptide includes the following structural formula X68:

-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
33. The compound of Claim 12 wherein said peptide is melittin.
34. The compound of Claim 12 wherein said peptide is an apidaecin.
35. A method of treating septic shock in a host, comprising: administering to a host a compound, said compound being a conjugate of: (i) a biologically active amphiphilic peptide, said peptide being an ion channel-forming peptide, and said peptide being capable of forming an -helix; and (ii) a conjugate moiety selected from the group consisting of: (a) carbohydrates; (b) proteins; (c) polyvinyl pyrrolidone; (d) polyalkylene glycols; and (e) polyvinyl alcohol, said compound being administered in an amount effective in treating septic shock in a host.
36. The method of Claim 35 wherein said conjugate moiety is a carbohydrate.
37. The method of Claim 36 wherein said carbohydrate is selected from the group consisting of dextran, hetastarch, hydroxyethyl starch, cellobiose, lactobiose, mannobiose, melibiose, lactobionic acid, and glucosamine.
38. The method of Claim 37 wherein said carbohydrate is dextran.
39. The method of Claim 37 wherein said carbohydrate is hetastarch.
40. The method of Claim 35 wherein said conjugate moiety is a protein.
41. The method of Claim 40 wherein said protein is selected from the group consisting of albumin and 2-macroglobulin.
42. The method of Claim 35 wherein said conjugate moiety is polyvinyl pyrrolidone.
43. The method of Claim 35 wherein said conjugate moiety is a polyalkylene glycol.
44. The method of Claim 43 wherein said conjugate moiety is polyethylene glycol.
45. The method of Claim 35 wherein said conjugate moiety is polyvinyl alcohol.
46. The method of Claim 35 wherein said peptide is selected from the group consisting of:
(a) magainin peptides;
(b) PGLa peptides;
(c) XPF peptides;
(d) CPF peptides;
(e) cecropins;
(f) sarcotoxins;
(g) a peptide including one of the following basic structures X31 through X37, wherein:
X31 is -[R31-R32-R32-R33-R31-R32-R32]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, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5;
(h) a peptide including the following basic structure X40:
R31-R32-R32-R33-R33-R32-R32-R31-R32-R32-R32-R34-R32-R32, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid;
(i) a peptide including the following basic structure X50:
R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41-, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophobic amino acid;
(j) a peptide including the following basic structure X52:
R42-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid;

(k) a peptide including the following basic structure X54:

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;
(1) a peptide including the following basic structure X56:
R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline;
(m) a peptide including the following basic structure X58:
-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R43' wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid;
(n) a peptide including the following basic structure X60:

R42-R42-R41-R41-R42-R42-R42-R41, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid;
(o) a peptide having a structure selected from the group consisting of:
(i) R41-R42-R42-R41-R42-R42-R41;
(ii) R41-R41-R42-R42-R41-R42-R42-R41;
(iii) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(iv) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and (v) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic amino acid or a neutral hydrophilic amino acid;
(p) a peptide being in an amide- or carboxy-terminated form, said peptide being represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide:
LeuLysLeuLeuLysLysLeuLeuLysLysLeuLysLysLeuLeuLysLysLeu or an analogue of said peptide wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from said peptide;
(q) a peptide including the following structural formula X62:
R41-R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid;
(r) a peptide including the following structural formula X64:
R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41, wherein R41 is a hydrophobic amino acid and R42 is a basic hydrophilic or neutral hydrophilic amino acid;
(s) a peptide including the following structural formula X66:
R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid;
(t) a peptide including the following structural formula X68:

-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid;
(u) melittin; and (v) apidaecins.
47. The method of Claim 46 wherein the peptide is a magainin peptide.
48. The method of Claim 46 wherein the peptide is a PGLa peptide.
49. The method of Claim 46 wherein the peptide is an XPF
peptide.
50. The method of Claim 46 wherein the peptide is a CPF
peptide.
51. The method of Claim 46 wherein the peptide is a cecropin.
52. The method of Claim 46 wherein the peptide is a sarcotoxin.
53. The method of Claim 46 wherein the peptide 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-;
X37 is -[R32-R31-R32-R32-R33-R31-R32]n-, wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic, basic hydrophilic, or hydrophobic amino acid, and n is from 2 to 5.
54. The method of Claim 46 wherein the peptide includes the following basic structure X40:
R31-R32-R32-R33-R34-R32-R32-R31-R32-R32-R32-R34-R32-R32' wherein R31 is a basic hydrophilic amino acid, R32 is a hydrophobic amino acid, R33 is a neutral hydrophilic or hydrophobic amino acid, and R34 is a basic hydrophilic or hydrophobic amino acid.
55. The method of Claim 46 wherein said peptide includes the following basic structure X50:
R41-R42-R42-R41-R42-R42-R41-R41-R42-R41-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
56. The method of Claim 46 wherein said peptide includes the following basic structure X52:
R42-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
57. The method of Claim 46 wherein the peptide includes the following basic structure X54:
R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R43-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
58. The method of Claim 46 wherein the peptide includes the following basic structure X56:
R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R44-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R44 is a neutral hydrophilic amino acid or proline.
59. The method of Claim 46 wherein the peptide includes the following basic structure X58:
R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R43-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
60. The method of Claim 46 wherein the peptide includes the following basic structure X60:

-R41-R42-R42-R42-R41-, wherein R41 is a hydrophobic amino acid, R42 is a basic hydrophilic or neutral hydrophilic amino acid, and R43 is a neutral hydrophilic amino acid.
61. The method of Claim 46 wherein the peptide has a structure selected from the group consisting of:
(i) R41-R42-R42-R41-R42-R42-R41;
(ii) R41-R41-R42-R42-R41-R42-R42-R41;
(iii) R42-R41-R41-R42-R42-R41-R42-R42-R41;
(iv) R42-R42-R41-R41-R42-R42-R41-R42-R42-R41; and (v) R41-R42-R42-R41-R41-R42-R42-R41-R42-R42-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic amino acid or a neutral hydrophilic amino acid.
62. The method of Claim 46 wherein said peptide is a peptide, being in an amide- or carboxy-terminated form, said peptide being represented by the following structural formula, and the numbers below each amino acid residue refer to the position of the residue in the peptide:
Leu Lys Leu Leu Lys Lys Leu Leu Lys Lys Leu Lys Lys Leu Leu Lys Lys Leu or an analogue of said peptide wherein at least one of amino acid residues 1 through 7, 9, 11, 12, 14, 16, or 18 is deleted from said peptide.
63. The method of Claim 46 wherein said peptide includes the following structural formula X62:
R41-R41-R42-R41-R41-R42-R42-R41-R41-R42-R42-R41-R42-R42' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
64. The method of Claim 46 wherein said peptide includes the following structural formula X64:
R42-R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41' wherein R41 is a hydrophobic amino acid and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
65. The method of Claim 46 wherein said peptide includes the following structural formula X66:
R41-R41-R42-R42-R41-R42-R42-R41-R41-R42-R42-R41-R41' wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
66. The method of Claim 46 wherein said peptide includes the following structural formula X68:

-R42-R41, wherein R41 is a hydrophobic amino acid, and R42 is a basic hydrophilic or neutral hydrophilic amino acid.
67. The method of Claim 46 wherein said peptide is melittin.
68. The method of Claim 46 wherein said peptide is an apidaecin.
CA002151046A 1992-12-07 1993-12-06 Treatment of septic shock with conjugated biologically active peptides Abandoned CA2151046A1 (en)

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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
WO1995000547A1 (en) * 1993-06-22 1995-01-05 E.I. Du Pont De Nemours And Company Antimicrobial composition of a polymer and a peptide forming amphiphilic helices of the magainin-type
WO1995019370A1 (en) * 1994-01-18 1995-07-20 Magainin Pharmaceuticals Inc. Ion-channel forming amphiphilic peptides having n-terminal modifications
GB9504761D0 (en) * 1995-03-09 1995-04-26 Unilever Plc Amphiphilic peptide and analogs thereof
KR100417183B1 (en) * 1995-03-22 2004-05-31 헨리 엠. 잭슨 파운데이션 포 더 어드벤스먼트 오브 밀리터리 메디신 Preparation of immunogenic constructs using soluble carbohydrates activated with organocyanidating agents
DE10112825A1 (en) * 2001-03-16 2002-10-02 Fresenius Kabi De Gmbh HESylation of active ingredients in aqueous solution
DE10209821A1 (en) 2002-03-06 2003-09-25 Biotechnologie Ges Mittelhesse Coupling of proteins to a modified polysaccharide
WO2005014655A2 (en) 2003-08-08 2005-02-17 Fresenius Kabi Deutschland Gmbh Conjugates of hydroxyalkyl starch and a protein
EP2252627B1 (en) 2008-01-24 2017-04-19 Esperance Pharmaceuticals Lytic domain fusion constructs and methods of making and using same
CN107320485A (en) 2008-10-02 2017-11-07 匹兹堡大学-属高等教育联邦体系 For the administration for the absorbent polymer for treating systemic inflammatory
WO2014070957A1 (en) 2012-10-30 2014-05-08 Esperance Pharmaceuticals, Inc. Antibody/drug conjugates and methods of use

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US5217956A (en) * 1988-10-21 1993-06-08 The Children's Hospital Of Philadelphia Composition and treatment with biologically active peptides and certain anions
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