SE9804614A0 - New peptides and use thereof - Google Patents

New peptides and use thereof

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Publication number
SE9804614A0
SE9804614A0 SE9804614A SE9804614A SE9804614A0 SE 9804614 A0 SE9804614 A0 SE 9804614A0 SE 9804614 A SE9804614 A SE 9804614A SE 9804614 A SE9804614 A SE 9804614A SE 9804614 A0 SE9804614 A0 SE 9804614A0
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SE
Sweden
Prior art keywords
medicinal product
peptide
prevention
peptides
formulated
Prior art date
Application number
SE9804614A
Other languages
English (en)
Other versions
SE9804614L (sv
SE9804614D0 (sv
Inventor
Inger Mattsby-Baltzer
Lars Baltzer
Lars Å HANSON
Original Assignee
A+ Science Invest Ab
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Publication of SE9804614L publication Critical patent/SE9804614L/xx
Priority claimed from SE9802441A external-priority patent/SE9802441D0/sv
Priority claimed from SE9802562A external-priority patent/SE9802562D0/sv
Application filed by A+ Science Invest Ab filed Critical A+ Science Invest Ab
Priority to SE9804614A priority Critical patent/SE9804614A0/sv
Publication of SE9804614D0 publication Critical patent/SE9804614D0/sv
Priority to AU50760/99A priority patent/AU752640B2/en
Priority to DE69937798T priority patent/DE69937798T2/de
Priority to US09/743,107 priority patent/US7253143B1/en
Priority to EP99935241A priority patent/EP1095061B1/en
Priority to PCT/SE1999/001230 priority patent/WO2000001730A1/en
Priority to AT99935241T priority patent/ATE381578T1/de
Priority to PT99935241T priority patent/PT1095061E/pt
Priority to DK99935241T priority patent/DK1095061T3/da
Priority to CA2333306A priority patent/CA2333306C/en
Priority to NZ509622A priority patent/NZ509622A/en
Priority to JP2000558131A priority patent/JP4488622B2/ja
Priority to ES99935241T priority patent/ES2299253T3/es
Publication of SE9804614A0 publication Critical patent/SE9804614A0/sv
Priority to HK01107436A priority patent/HK1036630A1/xx
Priority to US11/819,901 priority patent/US7803757B2/en
Priority to CY20081100292T priority patent/CY1108049T1/el
Priority to JP2009283513A priority patent/JP2010090162A/ja

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C07K5/04—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof containing only normal peptide links
    • C07K5/10—Tetrapeptides
    • C07K5/1019—Tetrapeptides with the first amino acid being basic
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/18—Peptides; Protein hydrolysates
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23J—PROTEIN COMPOSITIONS FOR FOODSTUFFS; WORKING-UP PROTEINS FOR FOODSTUFFS; PHOSPHATIDE COMPOSITIONS FOR FOODSTUFFS
    • A23J3/00—Working-up of proteins for foodstuffs
    • A23J3/04—Animal proteins
    • A23J3/08—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/08—Peptides having 5 to 11 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/04—Peptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • A61K38/10—Peptides having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/04—Antibacterial agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/10—Antimycotics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • C07K14/79—Transferrins, e.g. lactoferrins, ovotransferrins
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23V—INDEXING SCHEME RELATING TO FOODS, FOODSTUFFS OR NON-ALCOHOLIC BEVERAGES AND LACTIC OR PROPIONIC ACID BACTERIA USED IN FOODSTUFFS OR FOOD PREPARATION
    • A23V2002/00—Food compositions, function of food ingredients or processes for food or foodstuffs
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Medicinal Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Engineering & Computer Science (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Biochemistry (AREA)
  • Molecular Biology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Zoology (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Nutrition Science (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Toxicology (AREA)
  • Oncology (AREA)
  • Mycology (AREA)
  • Communicable Diseases (AREA)
  • Immunology (AREA)
  • Epidemiology (AREA)
  • Rheumatology (AREA)
  • Pain & Pain Management (AREA)
  • Urology & Nephrology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • General Preparation And Processing Of Foods (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)

Abstract

. •sOKANDE A+ Science Invest A13....,.. Box 3096 400 10 GOTEBORG UPPFINNARE 1. MATTSBY-BALTZER, Inger• Fortroligheten 23 413 46 GOTEBORG Ytterligare uppfinnare pi separat blad! BF,NAMNING NEW PEPTIDES AND USE THEREOF PRIORITET Svensk patentansokan 9802441-7, inlamnad 1998-07-06 Svensk patentansokan 9802562-0, inlarrmad 1998-07-17 AVDELAD/ UTBRUTEN Giltighetsdag Stamansiikans nr BILAGOR AVGIFTER rx1 Beskrivning Sekvenslista Oven pa diskett) Patentkrav Sarnmandrag Fulhnakt - Hanvisas till GF 2521/98 Anmalningsavgift Granskningsavgift utan ITS-granslcning Granskningsavgift rned ITS-granskning Extra kravavgift Bestallning av diariebevis Totalt x overlatelse Utlandsk text Prioritetsbevis Oversattning av priorbevis Forteckning Underfullmakt - Han visas till GF 2247/98 SEK800 6200 2600 x x 11 x x x SEK96

Description

_amw AV -AWAFl-UEPH LH 10 15 30 .zu-iz-nu ; 1o:ae m qoai louuous en 6 noouzöo;# u/ae 41531 15268 Ink t Patent- och regxesket 1998 -12- 2 3 HmmdbenKwmm7 2 toferrin and lactoferricin can be used for treatment and prevention of infections, inflammations and tumours.
EP-A-0 629 347 describes an antimicrobial agent con- taining (A) lacLoferrin hydrolysate and/or one or more of antimicrobial peptides derived from lactoferrins, and (B) one or more compounds selected from the group consisting of metal-chelaLinq protein, tocopherol, cyclodextrin, glycerin-fatty acid ester, alcohol, BDTA or a salt thereof, ascorbic acid or a salt Lhereof, citric acid or a salt thereof, polyphosphoric acid or a salt thsreof, chitosan, cysteine, and cholic acid as the effective com- ponents thereof. This anLimicrobial agent is intended for treatment of products, and especially for safely treating e.g. food and medicines. The agent according to this pub- lication is thus a new preservative. In the publication several peptide sequences are given and some of them re- semble the peptides according to the invention, although there are several important differences.
Even though native human lactoferrin and lactofer- ricin have been shown to have desired anti-inflammatory, anti-infectious and anti-tumoral properties they cannot be used clinically on a broad basis since Lhey are very expensive substances due to high production costs.
Summary of the invention The object of the present invention is to provide new peptides which can be used for the same purposes as lactoferrin and/or lactoferricin and which will have the same, or better, effects although being much cheaper to produce, The aim of the studies leading to Lhe present inven- tion was to design new peptides which could be taken up from the intestines. It has been shown Lhat humens in their brush border membrane have receptors which can bind to human lactoferrin (see e.q. Lönncrdal B., Lactoferrin receptors in intestinai brush border membranes, Adv. Exp.
Med. Biol., 1994, 357:l71-175). IL has also been shown LL-J-"a-.ff 1553:? e;usa-ryiasil^~iii~|i=aescufn'Kiwi-z9516513;.finn: _SANT AVIAWAPATENT 10 15 20 30 :zs-w-sß ; 10=5a n; 46:51 150000- 46 ö uøøuzzsøu: 'usa 4631 152268 Ink. t. Patent- och reuuemet 1998 *12- 2 Q Hmmdbænfimum ' 3 that bovino lactoferrin does not bind to Lhese recoptors.
Tho new peptidos should therefore rosemble human lac- Loferrin or human lactofierricin but they should also be easier and especially choaper to produce. Furthermore, thëy should be essentially as efficient as, or preforably more efficient than human lactoferrin or human lactofer- ricin in treatment and prevention of infections, inflam- mations and tumours.
IL was found that peptides consistinq of ll-17 amino acids comprising the sequenco with SRQ ID NO l given in the apponded sequenoe listing have the desired proper- ties. Tho peptides according to the invention correspond to the sequences that begin with one of the amino aoids in positions 15-21 and end with the amino acid in posi- tion 31, constituting human lactoferrin, although some of the counted from the N~terminal end, in the sequence amino acid residues may be modiiied in comparison with those of human lactoiorrjn. The sequence according to SEQ lD NO aoids 1 corresponds Lo the sequence formed of the amino in positions 21-31 in which some amino acids may be modified.
A plausible mechanism for the uptake of Lhese new peptides in the human body is thaL they are taken up in the intestine through binding to Lhe above montioned spe- cific lactoferrin receptors and are then transported through the circulation. Howevor, the invontion is in no way limited to this mechanism.
Thus, the present invention relates to new peptides with the sequences given in the appended soquence list- ing, and Lo funotionally equivalent homologues or ana- logues thereof.
Futthormore, the invention rolates to medicinal products and food stuff, especially in[anL formula food, comprising said peptidos.
The invention also relates to use of said peptides for the production of medicinal products for treatment and prevention of iníoctions, inflammations and tumours. 12 -Lbä I. F. : F; F; 112; k .Fl-LT'-.bI¿!š:.“-.i|.z-;;: \;.':«."v.2=.'-1-'.-'It.'.-* xiü-.ëífi -II- F _ 'mc SANT AWAWAPATENT :29-12-98 : 1e=se n; 4631 lsoofioe 46 a eseozsew 8/34 4631 ISÛÜEÜ Ink t. Patent- och regxemet 1998 »12- 2 9 upwdmn Kem f 4 The peptides according to the invention are fungi- cidal and bectericidal, and can thus be used ror other applications when substances with such properties are de- sired. They may for example be used as prcservativcs. lv The characterising features of the invention will be evident from the following description and the appended claims.
Detailed description of the invention 10 Thus, the invention relates to peptides coneisting of ll-17 amjno acids, comprisinq the soqucnce: F-X-W-X-R-X-M-R-K-X-R (SEQ ID NO 1) or functionally equivalent homologucs or anelogucs theroof- The single-letter and three-letter symbols used herein are well known to man skilled in the art, and have 20 the following mcaninq: F = Phe = phenylalanine, W - Trp = tryptophan, R = Arg = arginine, M = Met = methionine, and K 1 Lys _ lysinc. X = Xaa = any amino acid.
The amino acids denotcd by X or Xaa are prcferably, independently of each other, glutamine (Q or Gln), lysine 25 (K or Lys), aspartic acid (D or Asp), asparagine (N or Asn), or valine (V or Val).
Some of the peptidcs according to the invention are ”capped”, which means that the N-terminal end oi the pep- tide is acetylated, and the C-terminal end is amidated. 30 The Cäpped Version of SEQ ID NO 1 is thus: Ac-F-X-W-X-R-X-M-R-K-X-R~NH¿ In this sequencc Ac and NH2 denotes an acetyl (CH3CO-) Bb group and an amino group, respectively.
The advantage of the capped version, i.e. the sc- quence in which the amino and carboxy terminal ends have 'L 'di-If -ÖLÉZ | Ü t få fi Ü: '~. Vlåfi"'xïi'íi.ifri.\.:\liíåï ViT~\'JI.FÉFI'KFKÉ“ÉEt?1TfFÉ"Ü-l”\ï; . P-(T-C _SANT AVIAWAPATENT än 10 lb 20 30 35 :zs-lz-sa ; was n; 4631 lsooßoa 46 a eaeozssn: 9/34 4631 lsøøs mktfimmomfiuwfiü 1998 “12- 2 9 &wwflbnKßmn7 J been rcncted with acctylimidazole to form the amide CH3C0NH- or AGNH- and the free COOH at the carhoxy termi- nal end has been transformed into CONH2, is that this peptidc is neutral at the ends and thus has drasticaliy changed electrostatic properLies. Assuming that the re- ceptors bind the corrosponding sequences of human lao- toferrin where therc are no N- and C terminal charges, *the capped peptides should bind better as they in this respect resemble Lho native protein more than uncapped peptidcs- Under physiological conditions at a pH of ap- proximately 7, free amino and curboxy terminals would be ionised and the peptide would thus carry an extra posi- tive and an extra negative charqe.
A preferred group of peptides according to the in- vention consists of 14 amino acids. Those peptides corre- spond essentially to the sequence formed by the amino ac- ids in positions 18-31, counted from the N-terminal end, in the sequence constituting human lactoferrin, whercin some amino acids have been modified. The peptides in this group have the scquences SEQ ID NO 8-19.
The peptide according to the invention mostly corre sponding to this part of human lactoïerrin is the peptidc wiLh SEQ ID NO 8 given in the appendod sequencc listing.
The capped version of this sequence has SHQ ID NO 9.
The amino acid in position 3 in this sequcnce, i.e. a cysteine (C or Cys) may be replaced by an alanine (A or Ala) or a lysinc, the amino acid in position 5, a qlu- tamine, may be replaced by a lysine, the amino acid in position 9, an asparagine, may be replaced by an aspartic acid or a lysinc, and the amino acid in position 13, a valine, may be replaced by an aspartic acid.
When the pcptide according to the invcntion com- prises a cysteine, as the peptides with SEQ ID NO 4-J and 20~25, it may be advantageous to replace this cysteine by a acetamidomethyl-cysteine in order to avoid that the peptide forms a disulphide bridge with anoLher peptide I “'~."'7Jf-~~'| 9-4! É! lff- i ÉI Ü G : \ PJÉT'\_F'IFÉ-F\AI\E *.-.='E\É!T.'~'I"|"~.-"'~_["_QÉ;?§fi-1§;_.-=}{ê _['I|_'=|_"' cSÄNT AVIAWAPATENT LH 10 15 30 35 ;2s-12-sa ; 17:00 i; 4631 1sooeo~ 46 a eeeo2se;#1o/a4 4631 1 SIZJÛEB Ink t. Patent- och regxeflcet 1998 -12-» 2 9 huvudman .man f 6 comprising a cysteine. however, the amino acids glutamine and valine may then not be rcplaces as described above.
When the peptide according to the invention com- prises a lysine separated from an aspartic acid by three amino acids the lysine and the aspartic acid may form a lactam, as in SEQ ID NO 12 and 13, wherein a lactam is formed between a lysine in position 5 and an aspartic acid in position 9. It is also possible to obtain a di- lactam, as in SEQ ID NO 18 and 19, wherein a laetam ie formed between a lysine in position 3 and an aspartic acid in position 7 and another lactam is formed between a lysine in position 9 and an aspartic acid in position 13.
The lactam formation forces the peptide to adopt a three- dimensional structure that resemblcs that of the corre- sponding fragment of human lactofcrrin and this may aca complish better binding of the peptide to Lhe lactoferrin receptor.
A major advantage of Lhe peptides according to the invention is that they form the part, or a modified ver- sion of it, of the lactoforricin fragment of the human lactoferrin protein which the inventors have found to be active with regards to the invention.
An other advantage of the peptides according to the invention is that they are relatively short which means that they are cheaper and more easy to produce than longer peptides, such as lactoferrin itself.
The peptides according Lo the invention may be ei- ther of natural origin, e.g. derivcd from human lactofer- rin, or synthetically produced.
Apart from the above specified peptides it ie also possible to use Lunctionnlly equivalent homologucs or analogues thereof.
The peptides according to the invontion is suitable for treatment and/or prevention of infections, inflamma- tions and/or tumours. The term ”treaLment” used herein refors to curing, reversing, attenuating, alleviating, minímising, suppressing or halting the delotcrious of- l9flE~lÉ~ÉÜ 1h;¶H ¿:EWñT\N3RHAHUEÜÜÜUHiTï?ɶ? _Li_WFÄ _SÄNT AVIAWAPATENT LH 10 15 20 30 U.
L; 529-12-98 ä 17300 N 4631 150060* 46 8 6660286§#11/64 4631 15886 Ink. t. Patent- och regxezlæt 1998 -12- 2 9 :imanen mm f 7 focts of a disease state, disease progression or other abnormal condition, and the term ”prevention” used heroin refers to minlmising, reducing or suppressing the risk of developing a disease state or progression or other abnor- mal or deïetcrlous conditions.
The infections treatable with the peptides or me- dicinal products according to the invention include in- íections caused hy all kinds of pathogens, such as bacte- ria, viruses, fungi, etc.
It iS also possible to treat different types of in- flammations. Inflammation is a complex phenomenon marked i.a. by abnormal "redness" and swelling of tissues and organs, pain and heat in affected areas, capillary diln- Lation, leucocyte infiltration, cLc. Inflammation is pri- marily caused by exposure to bacterial and other noxlous agents and physical injury. Inflammation has many forms and is medlatcd by a variety of different cytokines and other chemical siqnals. These mediators of inflammation include tumour neerosis factor-u (TNF-a), interleukin-1 (IL-1), intcrleukán-6 (IL-6), interleukin-8 (IL-8), and various colony-stimulating factors (CSEs).
As stated above, the peptides according to the in- Vention are also suitable for treatment of tumours.
The peptides according to the invention may either be used as they are or be included in a medicinal product or a pharmaccutical prcparation. The medicinul product or a pharmaceutical preparation according to the lnvention may also comprise suhstanecs used to Lucilitate the pro- duction of the pharmaceutieel preparation or the admini- stration of the preparations. Such substances are well known to people skilled in the art and may for example be pharmaceutically ucceptable adjuvants, carriers and pre- servatives.
The peptldes or medicinal products according to the inventlon can be adminfisterod to a patient either sys- temioally or looally. The term ”patient” used herein re- latos to any person at risk for or suffering from a dis- l9§3«12~79 lïäïß 3:\PñT&HfiV\íN$\SEßUHTïKFI3JÜbCÉ.DÜÜ _SÄNT AV1AWAPATENT š29-12-98 ; 17201 M 4631 150060* 46 8 6660286;#12/34 4631 ISZZEÉ Ink. t Patent- och reguezket 1998 -12- Z Q Hmwüumnæmm' ease state, disease progression or othcr abnormal or 8 deleterious condition.
The systemic administration is suitable e.g. for treatment Of urinary tract infection, coljtis and tu- 5 mours. The systemic administration can be undertaken by oral, nasal, intravcnous, intraartcry, intracavitary, in~ tramuscular, subcutaneous, transdormal, suppositories (including rectal) or other rouLes known to those skilled in the art. Oral administration is preferred. 10 'The local administration is suitable e.g. for treat- mcnt of skin infections, all infections and inflammations in mucosal membrancs oLc. The local administration Can be undertaken by Lopical, oral, nasal, vagina] or cropharyn- qal route. For treatment of local infections or inflamma- 15 tions in the skin or mucosal membranes the peptides or medicinal products accordinq to the invention may c.g. be fl) included in a gel, a cream, an ointment, or a past In the method according to the invention an effecw tive amount of a peptide according to the invention is 20 administered to a patient. The term ”effective amount” used herein relates to an amount sufficient to treat or prevent a disease state, disease progression or other ab- normal or deleterious condition.
The peptides or medicinal products and methods ac- 25 cordinq to the invention are particularly well suited for treatment and/or prevention of urinary tract intention and colitis, but scvcral other inflammatory and infec tious diseases are also treatable accordinq to the pres- ent invention, Such as inflammatory bowel diseases, rheu- 30 matoid arthritis, conditions caused by the virus HIV-1, conditions caused by the virus CMV, and conditions caused by the fungi Candide albicans and Candida krusei. This listing is in no way Iimiting the scope of the invention.
The pcptidcs, medicinal products and methods accord- 35 ing to the invention are also well suited Lor preventive medical care by reducinq the risk of developing urinary tract infection or other lnilanmmtory or infectious dis- 1+@fi~1?-fia 1w=%» c;xtatxvswxhwsxcncunïwxrruwaætatto: SÄNT AVIAWAPATENT 10 15 30 :29-12-98 ; 17=o1 n; 4631 1sooeo~ 46 a eeøuzzsøma/m 4631 ZLSZÜS Int t. Patent- och regxelkei 1998 _12- 2 9 Hmm&bænKmmn7 eases in patients with an increased risk of attracting Q such complications.
Tho peptides, modicinal products and methods accord- ing to the invention may either be used alone, in combi- nation with each other or in combination with conven- tional therapy.
According to the present invention it is also possi- blc to include the peptides, in an effective amount, in any kind of food or beverage intended to reduce infec- tions and/or inflammations in patients running un in- creased risk of such conditions due to an underiying dis- ease Or a medical treatment.
For example, it is possible to include the peptides, in an effective amount, in an infant formuïa food intended to inhibit harmful effects Of bacteria, such as weight loss caused by inflammation induced by bacteria, viruses or iungi in infants. When the peptides according to the invontion is to be used in food stuffs, cially preferred to use peptidos of natural origin. e.g. for nutritional purposes, it is espe- Since the peptides according to the invention have antimicrobia] efiects they can also be used as preserva- tives in different food stuffs and medicinai products such as gels, creams, ointments, pastes, solutions, emul- sions etc.
Examgles In the examples below, ll peptides according to the invenLion are used, namely the peptides wiLh SEQ ID NO 2, 4, 6, 8, 9 11, 15, 19, 2l, 22, and 25. Below, tides are called Peptide 2, Peptide 4, 8, Peptide 9, Poptide 11, Poptide 15, 21, Poptide 22, and Peptide 25, similar referonces peptidcs, below called Reference l and those pop- Peptido 6, Peptide Peptide 19, Poptide rcspectively, Also Lwo Reference 2, are used.
Reference 1, a peptide with 10 amino acids, hus the soquence: Q-W-Q-R-N-M-R-K-v-R. 'i 1351:! 1.2 ZZ IUP. : fÄ-Ifl LT: V 'fT-"1Kffïf='L-Ä"I.'i'"'-..!.*.ïïtäfšïëí-V-'ï . FHIX-ff K f' ÉïJI' Mi: 2-2 "-_ IfLl-'í 57 _SÄNT AVIAWAPATENT (Il 10 lb 20 30 :29-12-98 ; 17=o2u 4631 1sooeo~ 46 a eseo2senn4/a4 4631 152868 Ink L Patent- och regxenkei 1998 -12- 2 9 Hmmäbænkmwnf 10 It thus resomhles the peptide according to the invontion with SEQ ID 2 (Poptide 2), with the excoption thai it lacks one amino acid, a phonvlalanine, at the N~terminal ond.
Reference 2, a pcptide with 18 amino acids, has the äequencez ofP-E-A-'r~K-c-F-Q-w-Q-R-N-M-R-K-v-R.
It thus resombles the peptide according to the invention with SEQ ID 24, with the exception that it includes one at the N-terminal ond. more amino acid, a glutamine, Tn the examples, the minimal microbicidal concentra- tions (MMC) and minimal inhibitory concentrations (MIC) were determined as follows, unless otherwise specified in the examples. Bactcrial or fungal strains were cultured in BHI medium over night at 37°C. A volumo of the culture was transferred to a new tube with BHI and incuhated for two more hours. Thereafter the cells were spun down and the pellet was suspended in BHI medium diluted 1/100 (1% BHI). The concentration of bacterial or fungal cells was spectrophotomotrically determlned at 650 nm. The micro- bial concontrations were also dotermined by viable counts. Peptides serially diluted in 1% BHI by twofold or tenfold steps were added in tripiicate to the wells of a microtiterplate (200 pl per well). The bacterial or fun- gal cell solutions were added in 10 ul volumes to give a final concontration of approximaLely 1-5 x 10” cells per ml in Lhe well. The microplate was incubates at 37°C in a humid Chamber for two hours. ThereafLer 5 ul was taken from each well and added as a drop onto a blood agar plate and incubated over night at 37°C. The microplato incubated for another 20 hourà at 37°C and thercafter Vlñfi analysed spectrophotomotrically at 650 nm in a microplate reader (Emax, Molecular Devices, USA). The concontration of poptide causing a 99% reduction of the inoculum after 2 hours of incubation was defined as the MMC”%. The Mlü value was defined us the concentration giving no increase 3:33 G2\PåTTfi$KEÅHö\ÜÜÜÜHÉV\VÉÉfiÜí&J.PÜC tSÄNT AV AWAPATENT .in š28-12-88 ä 17102 M 4631 150060* 46 8 6660286;#15/34 4631 1søøsø Ink. t. Patent- och regxerket 1998 ~12~ Z å fimmüumunaæm in the absorbance value above the background level after 11 20 hours of incubation.
Examgle J Tn this example, the microbicidal and microbiostatic activity of the peptides according to the invention were tcsted and compared to the Lwo references peptides.
C. (ATCC64549) and E. coli 06, tively, were incubated with the different peptides. The albicans respec- 10 experimente were performed with 1, 10, 25 and 100 pg/ml of pcptide. The results are shown in table 1.
Table 1 Peptide C. albicans R. coli MMCW$ MIC MMC%_ MIC Peptide 2 10 10 10 10 Peptide 4, A10 10 10 10 Peptide 6 10 10 10 10 Peptide 8 10 10 10 10 Peptide 9 10 10 10 10 Peptide 11 10 10 10 10 Peptide 15 25 10 10 10 Peptíde 19 10 10 10 10 Peptide 21 10 10 10 10 Peptide 22 25 10 10 10 Peptide 25 10 10 10 10 Reference 1 25 25 > 25 > 25 Reference 2 100 10 25 10 15 From the table, it is evident that the peptides ac- cording to the inventfion have heLter microbicidal and mi- crnhjostatic activity than the reference peptides. 20 Example 2 In this example the activities of the peptides ac~ cording to the invention on the killing of C. albicans .L-šüífi ~-'| 14-21? 15:24? »E1;\.t-=.;=_'1-'-.:-1_.~'.srßvi-Fe"\::t+n,:!r.'~1'fv-'aEüšaàfifišf-ßêfif.: jr." _SÄNT AV AWAFATENT 10 20 ,-29-12_9g ; 17:02 a,- 4631 1sooeo~ 46 a eeeo2ae;#1e/a4 4631 1522M58 Ink L Patent- och regxerket 1998 -12- 2 Q Hmmümmnfiumf and on the inhibition of the growth of C. albicans were studied. 12 C. albicans yeast cells (ÅTCC64549) were incubated for 2 hours at pH 4.5 in BHI medium diluted to 1% of the original concentrution containing 25 gg/ml of the pep- tide. Thcreafter the fungal solutions were cultured on blood agar platcs. OD@m was measured after incubation during an additional 18 hours.
The fungicidal effect of the peptides on C. albicans was determined as the ability of the peptide to kill 100% and 99%, respectively, of the fungus, while the growth inhibitory effect was determined by measuring the OD@0.
An jnhibitory effect existed when no increase in OD@Q was recorded. Tho results are shown in tablc 2.
Table 2 Peptide C. albicans killingz inhibition: 100% 99% Peptide 2 - ~ Peptide 4 + + L Peptide 6 -F + + Peptide 8 I + + Peptide 9 + I + Peptide 11 - + - Peptide 15 + + 1 Peptido 19 - + I Peptide 20 - + + Peptide 22 - + 1 Peptide 24 ~ + + Reference 1 - - - Reference 2 ~ _ “ killing: + f 100/99 % of the bacteria are killed - = less than 100/99% of the bacteria ere killed no increase in ODWO is scen ,|. = inhibition: - = ODüU continucs to increase 1.-;!-x-7-=I'-.t Lí-:ïïn o:'tx-za-1-\_:~1:'u=fams*\=;;s-:L':N'r'~f'\si:Ikërfï-'F- '-.:"f'.'.r 111 _SÄNT AVIAWAPATENT 10 ;29_12-93 ; 17:03 5 4531 15uueue 40 U uoouzuo;#1//ae 4631 1 SÜÛEÜ Ink. t Patent- och regneskei 1993 ~12~ 2 9 13 Hmmümmahumm' From the table, it is evident that the pepLides ace cording to the invention, especially Peptides 4, 6, 8, 9, and 15, have better effect on the killing and growth in- hibition of C. albicans than the reference peptides.
Examgle 3 In this example, the peptides according to the in- vention were used to study the effect on the killinq of different bacteria. The different bacteria used are shown in table 3.
The peptides were used at a concentraLion of 25 ug/ml.
The results are shown in table 3.
Table_ä Peptide Bacteria E. S. s. K- w faecalis epidcrmis aureus pneumoniae aeruginosa Peptide 2 + + + - - Peptide 4 I- + 4A + L Pcptide 6 F + L + + Pcptide 8 + + + + | Peptide 9 1 + | + + Peptide ll + + + + + Peptide 15 + -| + L + Peptide 19 + + + + F Peptide 20 + + + + | PepLide 22 + L + - ~ Peptide 24 L + I - - Reference 1 + ~ - ~ Reference 2 + + + - - + - 99% of the bacteria are killed - = less than 99% of the bacteria are killed 'rä-ï-ßI-š--ïlë- Iäfïl ZIJ-.ï-:ï-Já-If -tï=*-.1ï'š'-.'1' KL-:Lfff\.fe1~?:L=“~.=L;fin1:1~1T\:"._;_=3Jfulrm-:fß--j-:j- sÄNT AWAWAPATENT ;2a-12-as ; 1v=uu -; m1 muumf -w u \~~u«~~-~~f~» 4631 ISZÜEZ Ink. L Patent- och regxelket 1998 ~12~ 2 9 Hmmäbænlßmmï 14 From the table, it is evident that the peptides ac~ cording to Lhe invention, especially Peptídcs 4~20, have better effect on the killing of bacteria than the refer- ence peptides.
|-'I,=-'I1:-ï----'!-«Lz-;-= Ilêuíßíé' xßfx-'rakiíuxïzuanzüzßøuïmxv'\.f?L:.4J¿lE.f1-è. mini". rSÄNT AV IAWAPATENT <120> ;28-12-98 š 173031; 4631 150060* 4631 lšßßßi 15 SEQUENCE LTSTING A+ Science Tnvest AB New peptidas and use thcregf 2986569 5Ü~ 9802441-7 <150> ¿151> d170> <2lOb fi2]1> fl?12} fi213> <22Û> <1 2 2 3 I:> »f 4 o 0::- 5 “ 1998-OY-06 9802562-O 1998-07-17 25 Patentïn Ver. 2.0 1 ll PRT Artíficial Sequencc Description ot ArLLficial Sequence: natural or ~rLiIicial origin, corrnponding tg a modifigd version UI tha sequence cunsistlng of amino acids 21-31 in human 1dgLQfçrr1n 1 Phë Xaa Trp Kaa Arg Xan MQL Arg Lys Xaa Arg l få? '1 O I:- fi211> fl2l2b ¿2l3§ d220> <223> 5 10 2 11 PRT Å?tiIiciaL Sequcncé Description of Artificial Sequence: natural of arLificial origin, correponding Lo the sequcnce conslsting of amino acids 21-31 in human lactoferrin 46 8 6660286 2 #19/34 Ink L Patent- och regxezket 1998 »1 2- 2 9 âiuvudfaxen .Kassan 7 » . . _ _ . . . Q ?#2Û/34 'SANT AV_AWAPATENT ,29 12 98 , 17.q4Å, 4631 ISÛÛÖÛ 46 8 666Û286 4531 lsøøså Ink. L Patent- och regxeflm *G98 -12- 2 9 <400> 2 Huvudfanem .Knssæ 7 Phe Gln Trp Gln Arg Asn Met Arg Lys Val Arg 1 5 10 <210> 3 ¿2ll> ll <2l2> PRT <213> Artificial Sequence <220> <221> Moo_REs <222> (1) <223> ACETYLATION <220> <221> MoD_REs <222> (ll) <223> AMIDATION <223> Description of Artificial Sequence: natural or artificial origin, correponding to a modified version of the sequence consisting of amino acids 21-31 in human lactoferrin <400> 3 Phe Gin Trp Gln Arg Asn Men Arg Lys Val Arg 1 5 10 <210> 4 <2ll> 12 <212> PRT <213> Artifícial Sequenca <220> _ <223> Description of Artífioial Sequence: natural or artificial origin, correponding to che sequencc consisting of amino acids 20-31 in human lactoferrin <4U0> 4 Cys Phe Gln Trp Gln Arg Asn Met Arg Lys Val Arg 1 5 10 <210> 5 SÃNT AV IAWAPATENT_ <2ll> <212> <213> <22o> <22l> <22z> <223> 42205 <22l> <222> <223> <220> <223> <400> ;29-12-98š 171041; 4631 15ø@sø ' 17 ink, z. Pazem- och regnade; 12 1098 #12* 2 Q PM Havudíaacen .ksidß/ Artificíal Sequence MoD_Rss (1) ACETYLATION Moo_Rßs (12) AMIBATION Description of Artificial Sequence: natural or artificial origin, correponding to a modified version of the sequence consisting of amino acids 20-31 in human lactoferrin 5 Cys Phe Gln Trp Gln Arg Asn Met Arg Lys Val Arg 1 <2l0> <211> <212> <213> <220> <400> 5 10 6 13 PRT Artificial Sequence Description of Artificial Sequencet naLurdl ur artificial origin, correponding to the sequence çonsisting of amino acids 19-31 in human lactoferrin 6 Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Lys Val Arg 1 <2lOm <2ll> ¿2l2> <2l3> <220> <22l> 5 10 7 13 PRT Artificial Sequence MøD_Rss 4631 150060* 46 8 6660286 š #21/34 SÄNT AVIAWAPATENT š29-12-88 š 17104 l; 4631 150060* 46 8 6660286§#22/34 4631 15@B6@ Ink. t Patent- och reg.vem_ -=.2zz> m 1998 "n" 2 g <22]> ACETYLATION ßjgvgdfmgen Kgggm/ '\ 220 ¿21> MOD_REs a222> (13) 223> AMIDATION <223> Description of Artificial Sequence: natural or arcificial oriqin, correponding to a modified version of the sequence consisting of amino acids 19-31 in human lactoferrin <400> 7 Lys Cys Phe Gln Trp Gln Arg Ash Met Arg Lys Val Arg 1 5 10 <210> 8 <2ll> 14 <2l2> PRT <2l3> Artificial Sequence <220} <223> Description of Artificial Sequence: natural or artificial origin, correponding to the sequence consisting of amino acids 18-31 in human lactoferrin <400> 8 V Th: Lys Cys Phe Cln Trp Gln Arg Asn Met Arg Lys Val Arg 1 5 10 '<21o> 9 <21í> 14 <212> PRT <2l3> Artificial Sequence <220> <221> MOD_RES <222> (1) <223> AcETïLAT1oN- <22o> <221> Moø_Rßs <222> (14) SÄNT AVIAWAPATENT <220> <223> <400> §23_l2-98 ä 17304 H 4631 1sø@sø 19 |n|<. z. Patent- och regxeflæi - AMIDATIoN ïsäâ 42"' 2 g Hmmdhm Ha¥m7 Éescription of Artificial Sequence: natural or artificíal origin. correponding to a modified version of the sequence consisting of amino acids 18-31 in human lactoferrin 9 Thr Lys Cys Phe Gin Trp Gin Arq Asn Met Arq Lys Val Arg <2lO> <21l> <2l2> <213> <220> <223> <40ü> 5 10 10 14 PRT Artíficial Sequence Description of Artificial Sequence: natural or artificial origin, correponding to a modified version of the sequence consisting of amino acids 18-31 in human lactoferrin 10 Thr Lys Ala Phe Lys Trp Gln Arg Asp Met Arg Lys Val Arg 1 <210> <21l> <312> <213> <220> <221> <222> fi223> <220> <22l> <222> <223> <220> <223> 5 l0 ll 14 PRT Artificial Sequence MoD_REs <1) ACETYLATION MoD_REs (14) AMIDATION -Description of Artificial Sequence: natural or artificial origin, correponding to a modified version of the sequence consisting of amino acids 4631 IDUUUU* “H3 O UUUULUUnfLU/ui 0 SÃNT AV IAWAPATENT <400> ;2S-12-98; 171041; 4631 152268 ZU 18-3] in human lactoferrñn 11 4631 150060* 46 8 6660286;#24/34 lnlc t Patent- och regxellšfli 1998 42- 2 9 ß-lpvudfmcen Kassan f' Th: Lys Aïa Phc Lys Trp Gln Arg Asp Mat Aïq Lys Val Arg 1 ¿2lO> <211> c212> §213> 5 10 12 “ 14 war Artificial Sequcnce {220> f223> Description oí Artificial Sequcnce: natural or arLificial origin, correp. to a modified version of the sequencc cønsisLing of aa 18-31 in human lflctofêrrin; Q laCLam is tormed between aa 5 and 9 fl220> fl22l> ß1NDING ¿222> (ß>..<9> <4OÜ> 12 Th: Lys Ala Phe Lys Trp Gln Arg Asp Met Arq Lys Vn1 Arq 1 5 10 fi2lOm 13 <2ll> 14 {2l2> PRT C213> Artificial Sequencc fi220> fl22l> fl222ß æ223> {220> -fi2 2 'I 1:» <222> 4223> X: IU I\.\ .NI h) I\.\ N' |-'- C- \_.' \,' 'V §220D fiïšßb Mc>D_R.ES ( l) ACÉTYLATION MoD_ums (14) AMIDATION RINDING (5)--(9) Dascríption of ÄrLi[icial Sequencc: nä LLllTül. OT š28-12-88 š 17205 M 4631 150060* 4631 ISZÜBÜ 21 SÄNT AVIAWAPATENT artifficiaï origin, correp. to a modified version of Lhe sequence cunsisting of aa 18-31 in human Jaotoferrin: a lactam is formed b@Lween aa 5 and 9 64003 ?3 THE LVS Älâ Phê Lyä Trp GIH Åfg Afip Met Arg LY5 VJ1 Arg l 5 10 ë2l0> 14 <2l1> 14 ¿2l2> ERT 42l3> Artificiai Sequence <220> fi223> Description of Artificíai Sequence: natural or arLificial origin, corrcpondinq Lo a modified version of tha scqumnce consisLing of amino acids 18-31 in human lacLoEerrin <400> 14 Thr Lys Lys Phe Lys Trp Gln Arg Asn Met Arg Lys Val Arg 1 5 10 <210> 15 {211§ 14 <212> raw fi2l3> Artificial Sequence <220b 42213 ü¶??> fi2235 MoD_REs U) ACETXLATION N* -._I. 5 MOD_RÉS (W4) AMTDATION Å) |\.'l |\J F) .\} k) |\.) UC' F) i-' Û 'V' “i / å. 1\) l\} \ I Description of Artificíal Saqueflcé: naLural or arLiIicial origin, corrcponding to a modified Vêrßiøn OI Lhe sequence consistíng of amiga açids 18-31 in human 1acLoIerrin <400b 15 Thr Lys Lys Phe Lys Trp Gln Arg Asn Mot Arg hyfi val Arg 46 8 6660286;#25/34 1998 -12» 2 ß HWNÜÜH Human/ SÄNT AV AWAPATENT ;29-12-98 ; 17205 M 4631 150060* 46 8 6660286;#26/34 4531 15øø§@ Ink L Patent- och regyem 1998 »12- 2 s 1 n 10 ämm I, <210> 16 <2ll> 14 -112 12) PRT 42l3> Ärtificjaï Sequcncc <220> Uescriptinn of Artificial Scqucnce: naturaJ or artificial origin, corrcponding to n modified vcrsfinn of the sequence consisting of amino acids lü-31 in human lacLoIerrin fi400> 16 Thr Lys Lys Phc Gln Trp Asp Arg Lys Met Arq Lys Asp Arg 1 5 10 fi210> 17 :211> 14 -:.'.7.'l 7..'.> PRT <213> ArtificiaL Sequence {2"> Description of Artificial Scqucncn: naturaï or artiticiai origin, corrcponding to a moditied version of the scqucnce consistinq of amino acids 18-3] in human lactnfcrrín -=:I.'220> .12122 l T* MÖL7__ (1) f-f 2 23 21- ACETYLAT IGN fi?20> flz21> MoD_REs {222> (14) flfzzfšï' ÄMLDÅTION <400> 17 Thr Lys Lys Phe Gln Trp Asp Arg Lys Met Arg Lys Asp Arg l 5 10 <21o> 18 <211> 14 fi212> rxw SÃNT AVIAWAPATENT N W u; 'ä220> <223> . Å Å IV N N N N N Q F C \\_/ \/' ë220> fi22l> í222} fi40Û> 'v Artificial Sequence š29-12-88 ; 17205 M 4631 150060* 4631 ISÜÜEÉÉB mktFm¶fi1mhnmNmmfi 10998 42- 2 s Üuflßfimißhwflgi DQfifir1pLiOn of Artíficial Sequcncç:naLufa1 ur artificial origin, corrcp_ to a mvdified vers. of the scq. consisting of aa 18-31 in human JäflflOfêï*iD: lacLams formed between aa 3 and 7, and aa 9 and 13 ß1Nu1NG (3)--(7) BLNDLNG (9)..(l3) 18 Thï Pyå Lys Phe Gln Trp Asp Arg Lys Met Arg Lys Agp Arg ¿220> ë22l> f222h §223> \ '20> <22l> 5 |\ <222> fl723> <220> qzzly ë222> 5 10 19 14 PRT ArLlficial Sequence Deflcription OI Artififiial Süquençeznatural 0: mrtififlinl Orígín, cutrep. to a modified vers. of Lhe seg, uonsistinq of aa 18-31 in human lactoferrin; lactams formed between aa 3 and 7, and aa 9 and 13 Mou_ums (1) ACETYLATION MoD_Rßs (14) AMIDATIQN BLNULNG (3>..(7) 46 8 6660286§#27/34 SÃNT AV IAWAPATENT <220> §22l> fi222> ;29-12-88 ä 17105 M 4631 150060* 4631 lšgåßß Ink t. Patent- och regmgkeg 1998 ~12i g g ßïnmue B-luvudfnm MW, ; (9)..(l3) fl400> 19 Thr Lys Lys Phe Gln Trp Asp Årq Lys Met Arg Lys Asp Arg l <210> -:_'_ l j» i2l2ß <220h fl223b fi400> 5 10 20 15 PRT Artificial Sequcnce Dëåüïlptiøn Of ArLlfiCial Sequencqg naLural Or artificial origin, correponding ta the scquence consisting of amino acids l7-3] in human lactofarrin 20 Alm Thr Lys Cys Phe Gln Trp Gin Arg Asn Met Arg Lys VaL Arg a2lU> ¶2il> ¶2l2> fl213> fi220} <221} ¿222b {223> {220> ¿271> fl222> fi223> .-'\. 3.2 -.\: h; N I--J LI O {400> 5 10 15 21 15 ERT Artificial Sequenue Morsjuzs (1) AcETvLATioN Mon_1u-;s: (15) Am: DAT 1 om Dnscription of Aftífiuial Scquence: natural Ur artificial origin, correpondinq io a modified version of Lhe scquence Consisting of aminn acids 17-31 in human lactofcrrín 21 Aïm Thr Lys Cys Phe Gin Trp Gln Arg Asn Met Arg Lys val Arg IG 46 8 ÖÜÖUZÖÖÉFZÖ/dä SÄNT AVIAWAPATENT <2lO> fl2ll> fl212> fi213> {220> {223> <400> Glu A 1 fl?10> íßllß í2l2> ífillš <220> 4221: fl222> {22Û> §220> «2m1> 4222: í22H> <22Û> {223> -22 4 f) Û2> Glu A l fi210b fl2ll> 4212» 17106 M 4631 150060* 15Û@6@ ;2S-12-88 ; 4631 25 15 22 16 PRT Artifícial Scquenne DëSCript-iÜn Of 00211 sCquênfljçš; natuyäl Or artifigial Ofigínf correpnnding to the Sequcnca C°n$ï5ïiHG Of amino acids 16-31 in human ïactoíerrin 22 Ia Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Lyg va1 Arg 5 10 1: 23 16 PRT Artificial Sequence Mou_REs (1) ACHTYLATION b4OD_RE:'-3 (16) AMIDATIQN Û$5CfiDtiOfl Of AItifjCiñ1 Éequcncê: natural or arLificial oriqin, correpunding tm a modifigd version of the sequence consisLing of Amina acids 16-31 in human lactofcrrin 23 lä Thr Lys CYS Phe Gln Trp Gln Arg Asn Met Arg Lys Val Arg 5 lo 15 24 17 PRT ll 46 8 6660286;#2S/34 Ink. t. Patent- och regxerket 1998 -12- 2 9 lflnmäbæn Namn ' SÄNT AVIAWAPATENT :29-12-88 ; 17 206 l; 4631 150060* 46 ö uubuzzsonruu/.Ja 4531 ßøåšø mk f. Paæm- och Ingå/em 1993 -12- 2 9 ÜWUdfflmn .Kassan r fi213> ÅwLifíuial Sequence {220> fi223> Description of Artificial Scqucncc: natural op artificial origin, correponding tm Lhe gequence mïolïsílsiïñfhg (JF, .än1ïf1zj> açids 15-31 in human lautoferrin fi400> 24 PIO CTU Åïa Th? Lys Cys Phe Gin Trp Gln Arg Asn Met Arq Lys Val 'I 5 10 15 Arg ¿2l05 25 <2l1> 17 PRT <213> Artificial Sequence @220> {22l> MOD_RES «222> (11 -:,1?.2 3;- ALTETYJZAT 'ITON ~'-ï 2 2 l 11' MOD_RES '2> (17) fl223> AMIDATION -='.I.')..')..'%> T)c-'=.:=:<".r'|pl_ ïrim m1' År! 'x fïzyiaï Eïecluençe: natulral gr arLlficial oriqin, correponding to a modified version of the sequence consisting of amino ncíds 15-31 in human ïactofcrrin <400> 25 PPG Glu Ala Thr Lys Cys Phe Gln Trp Gln Arg Asn Met Arg Lys Val l E: 'l O 15 Arq 12

Claims (11)

1. SNW'MFAWTNfiWT 'IJI lO 20 30 in 728-12-88 7 17 061; 4631 152869 4631 150000* 46 6 ubouzöofißai/aa Ink. t. Patent- och ramverket 27 1999 ~12~ 2 s cLAIMs liuwdfmæn mm l. A peptidc c0nsisLing of ll - 17 amino acids com- prisinq the soquonco wiLh SEQ ID NO l, or Iunctionally equivalent homoiogues or analogues theroofl. acids denoted hy xaa are, K, D,
2. A peptide according to claim l, wherein the amino independently of each other, Q, Or V. N,
3. A peptide according to ciaim 2, having one of Lho sequences SEQ TD NO 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 21 or 24, or functionally equivalent homologues or ana- logues thereof.
4. A peptide according to claim 3, having one of the soquences SEQ LD NO B, l0, 12, 14, 16 or 18, or function- ally equivalent homologues or anaïogues tnereof.
5. A peptide according to cïaim 2, wherein the N- terminal amino acid is acetylated and/or tho C-torminai amino acid is amidated.
6. A poptide according to claím 5, having one of the sequences SEQ ID No 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23 or 25, or functionally equivalent homologues or ana- logues thereof.
7. A peptide according Lo ciaim 6, having one of the sequences SEQ TD NO 9, 11, 13, 15, 17 or 19, or function- ally equivalent homoloques or analogucs thoroof.
8. A peptide according to cluim 1 or 2, having a so- quenoe essentially corresponding to one of the sequences SEQ TD NO 4-9 or 20-25 but whcroin Lhe cysteine has been replaced by a acetamidomethyl-cysteine, or functionally equivalent homologues or analoques thereoi. 9. A medicinal product comprisinq a peptide accord- ing to any of the claims 1-8. 10. A modicinal product according to claim 9 for treatment and/or prevention of infections, inflammations and/or tumours. 11. A medicinal product according to claim 10, for treatment and/or prevention of urinary tract inloction. .Ü : 33 ~.-2 '. \1-'1\'.l'\.b!.iiL<.\.Al\L21L-.GEIZUETIIV3.¥=“~.2iÄ!f3F.-ï1-í-I? . ïf-flfllf' SÄNT AVIAWAPATENT 10 15 20 25 30 š23-12-98 § 171071; 4631 ISZÉSÛ 45531 IDUUDU* Ink. t. Patent- och reguerket w9842~2§ flmmdoænflmam * A medicinal product according to claim 10, for 28 12. Lrcatment and/or prevention of colitis. 13. A medicinal product according to any one of the claims 9-12 formulated for oral administration. 14. A medicinal product according to any one of the claims 15.
9. -12 Lormulated for parentera] administratior. A medicinal product according to claim 14 formu- lated fOr tøpícai administration. 16. A medicinai product according to any one of the claims 9-15 formulated for administraLion on mucosal mom" branes. 17. Food stuii comprising a peptide according to any of the claims 1-8. 18- Food stuff accordinq to oiaim 17 being an infant formula food. 19. Use of a peptide according to any one of the ciaims 1-8 for the production of a modicinai product Ior treaLmont and/or prevention of infections, inflammations and/or tumours. 20. Use according to c1aim 19, wherein the medicinal product is intended for treatment and/Or prevention of urinary tract infection. 21. Uso according to claim 19, wherein the mediflinal product is intended for treatment and/og prevention of coiitis. 22. whcrcin 19-21, oral ud- Use according to any one of the claims the medicinal product is formulated for ministration. 23. wherein 19-21, par- Use according to any one of the oïaims the medicinal product is formulated for enteral administration. 24. Use according to claim 23, whcrcin the medicinai product is formulated for topical administration. 25. Use according to any one of the claims 19-24, wherein the medioinal product is formulated for admini- StratiOU OT! mlJCOFi-ål IHëmbIïlHëL-ï. ' 'ff »2219/ '_|_._| z ffaïå GI: 'E í-"ï"\'l" “'_ï\!.*ï ?ï 13-1932: 4D Ö ÜÜUU¿OÜ v ¥HJ¿/ dä! SÄNT AVIAWAPATENT 10 15 20 25 ;29-12-88 ; 17 07 M 4631 TSÜESB QÖEJI IOUUOU* “HJ O uuuuruuvff-uur o: Ink. t. Patent- och ramverket 1998 -12- 2 Q 29 HmmdoænKæwn' 26. Use according to claim 27, wherein the modicinal product constitutes or is included in a food stuff. 27. Use according to claim 26, wherein the food stuff is an infant formula food. 28. A method for troatmcnt or prevention of infoc- tions, inflammations or tumours wherein an effective amount of a substance chosen irom the group conåifltiflg Of the peptides having any of the sequences SEQ ID NO 1-25, rragments, and functionally equivalent homologues and analogues thereof, is administcrcd to a patient. 29. A method according to cluim 28 for LrCàLmCnL and/or prevention of urinary tract infection. 30. A method according Lo ciaim 28 for treatment and/or prevention of colitis. 31. A method aßcordinq to any one of the claims 28, whorein the Substance is orally administered. 32. A method accordinq to any one of the claims 28, wherein the Substance is parenterally administered. 33. A method according to cïaim 32, wherein the sub- stancc is topically administered. 34. A method according to any one of the claims 33, wherein the substance is administered on mucosal mem- branes. 35. A method according to claim 31, wherein the sub- stance is included in food stuff. 36. A method according to claim 35, wherein the sub- stancc is inciudcd in un infunt Iormula food. liæfl~1z~zæ iß=ia u \:sw«msz\ims\ssfiuw1vurasea:ar.““" DAN! AV-AWHFAIENI
10. ;zu-1z-uu ; 1/=u1l; 4ua1 iauunufl 4531 1SZEÜ Ink. t. Patent- och reqxerket 30 1998 -12~ 2 å The invention rclates to now peptides consisting of
11. - 17 amino acids comprising the soquence with SRQ ID NO 1, or functionally equivalent homologues or dnulogues thereof. The invention also relates to medicinal products comprising such peptides, especially intended for treat- mcnt and prevention of iníections, inflammations and tu- mours. Furthermore, Lhc invention relates to food stuff, c.g. infant formula food, comprising the above mentioned peptidos. QD Ö UDOUZÖUš#U4/Då
SE9804614A 1998-07-06 1998-12-29 New peptides and use thereof SE9804614A0 (en)

Priority Applications (17)

Application Number Priority Date Filing Date Title
SE9804614A SE9804614A0 (en) 1998-07-06 1998-12-29 New peptides and use thereof
CA2333306A CA2333306C (en) 1998-07-06 1999-07-06 Peptides based on the sequence of human lactoferrin and their use
NZ509622A NZ509622A (en) 1998-07-06 1999-07-06 Peptides based on the sequence of human lactoferrin and their use
DE69937798T DE69937798T2 (de) 1998-07-06 1999-07-06 Peptide, basierend auf der sequenz des menschlichen lactoferrins und ihre anwendung
ES99935241T ES2299253T3 (es) 1998-07-06 1999-07-06 Peptidos basados en la secuencia de la lactoferrina humana y sus usos,.
PCT/SE1999/001230 WO2000001730A1 (en) 1998-07-06 1999-07-06 Peptides based on the sequence of human lactoferrin and their use
JP2000558131A JP4488622B2 (ja) 1998-07-06 1999-07-06 人ラクトフェリンの配列に基づくペプチドおよびその使用
US09/743,107 US7253143B1 (en) 1998-07-06 1999-07-06 Peptides based on the sequence of human lactoferrin and their use
EP99935241A EP1095061B1 (en) 1998-07-06 1999-07-06 Peptides based on the sequence of human lactoferrin and their use
AU50760/99A AU752640B2 (en) 1998-07-06 1999-07-06 Peptides based on the sequence of human lactoferrin and their use
AT99935241T ATE381578T1 (de) 1998-07-06 1999-07-06 Peptide, basierend auf der sequenz des menschlichen lactoferrins und ihre anwendung
PT99935241T PT1095061E (pt) 1998-07-06 1999-07-06 Péptidos baseados na sequência da lactoferrina humana e sua utilização
DK99935241T DK1095061T3 (da) 1998-07-06 1999-07-06 Peptider baseret på sekvensen af humant lactoferring og deres anvendelse
HK01107436A HK1036630A1 (en) 1998-07-06 2001-10-24 Peptides based on the sequence of human lactoferrin and their use
US11/819,901 US7803757B2 (en) 1998-07-06 2007-06-29 Peptides based on the sequence of human lactoferrin and their use
CY20081100292T CY1108049T1 (el) 1998-07-06 2008-03-14 Πεπτιδια με βαση την αλληλουχια της ανθρωπινης λακτοφερρινης και χρηση τους
JP2009283513A JP2010090162A (ja) 1998-07-06 2009-12-14 人ラクトフェリンの配列に基づくペプチドおよびその使用

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SE9802441A SE9802441D0 (sv) 1998-07-06 1998-07-06 New peptides and use thereof
SE9802562A SE9802562D0 (sv) 1998-07-17 1998-07-17 New peptides and use thereof
SE9804614A SE9804614A0 (en) 1998-07-06 1998-12-29 New peptides and use thereof

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WO2005090388A1 (en) 2004-03-19 2005-09-29 The University Of Queensland Alpha helical mimics, their uses and methods for their production
US7183381B2 (en) 2004-10-26 2007-02-27 Agennix, Inc. Composition of lactoferrin related peptides and uses thereof
BRPI0620806B8 (pt) * 2005-12-30 2022-07-05 Evonik Roehm Gmbh complexo e composição compreendendo um peptídeo e uma molécula carga, e uso da referida composição
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WO2000001730A1 (en) 2000-01-13
AU752640B2 (en) 2002-09-26
SE9804614L (sv) 1900-01-01
DK1095061T3 (da) 2008-04-21
CY1108049T1 (el) 2012-05-23
PT1095061E (pt) 2008-03-10
SE9804614D0 (sv) 1998-12-29
US7253143B1 (en) 2007-08-07
ATE381578T1 (de) 2008-01-15
EP1095061A1 (en) 2001-05-02
ES2299253T3 (es) 2008-05-16
JP2010090162A (ja) 2010-04-22
JP4488622B2 (ja) 2010-06-23
US7803757B2 (en) 2010-09-28
NZ509622A (en) 2003-05-30
DE69937798D1 (de) 2008-01-31
EP1095061B1 (en) 2007-12-19
US20080299180A1 (en) 2008-12-04
DE69937798T2 (de) 2009-04-30
AU5076099A (en) 2000-01-24
HK1036630A1 (en) 2002-01-11
CA2333306A1 (en) 2000-01-13
CA2333306C (en) 2011-12-06

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