WO1998029445A1 - DERIVES α-AMINO-BUTYRATE DES VENINS - Google Patents

DERIVES α-AMINO-BUTYRATE DES VENINS Download PDF

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Publication number
WO1998029445A1
WO1998029445A1 PCT/EP1997/007333 EP9707333W WO9829445A1 WO 1998029445 A1 WO1998029445 A1 WO 1998029445A1 EP 9707333 W EP9707333 W EP 9707333W WO 9829445 A1 WO9829445 A1 WO 9829445A1
Authority
WO
WIPO (PCT)
Prior art keywords
abu
peptide
homologous
venom
amino
Prior art date
Application number
PCT/EP1997/007333
Other languages
English (en)
Inventor
Jean-Marc Sabatier
Modhammed El-Ayeb
Jurphaas Van Rietschoten
Hervé Rochat
Original Assignee
Armel S.A.
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
Application filed by Armel S.A. filed Critical Armel S.A.
Priority to GB9915067A priority Critical patent/GB2335923B/en
Priority to AU58611/98A priority patent/AU5861198A/en
Publication of WO1998029445A1 publication Critical patent/WO1998029445A1/fr

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Classifications

    • 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
    • C07K14/43504—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates
    • C07K14/43513—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae
    • C07K14/43522—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from invertebrates from arachnidae from scorpions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies

Definitions

  • the invention relates to synthetic peptides which have amino acid sequences derived from naturally occurring animal or plant venoms but which incorporate ⁇ -amino-butyric acid residues, and to preparations containing the said synthetic peptides.
  • Such synthetic peptides may have prophylactic and therapeutic uses, and these uses are included within the scope of the invention.
  • Toxin inoculation essentially neurotropic, is responsible for envenomation which exerts a neurotoxic activity altering the action potential of nerves and muscles.
  • Scorpions toxic to human beings and other mammals, are essentially represented by the following four species: Androctonus, Buthus, Tityus and Centruroides . Every year, world wide, there are approximately 150,000 incidences of human beings being stung by scorpions. 1,200 of these result in fatalities. In North Africa, scorpions of the species Androctonus are responsible for 80% of the incidences and 95% of the deaths.
  • the scorpion neurotoxins which are lethal to mammals are basic peptides made up from 60 to 70 amino acid residues cross-linked by four disulphide bridges. Their target is the sodium potential depending channel of excitable cell membranes. There is a structural homology in toxins which determines a protein with specificities. However there is an antigenic polymorphism mainly among the proteins of this family.
  • Classic treatment of envenomation is based on a poly specific serotherapy, the specific antibodies of which are obtained by a mixture of appropriate venoms of several scorpion species living in the same geographic area.
  • a venom fraction enriched with toxins can be used in order to improve this serotherapy.
  • this serotherapy is limited, because the toxins are so effective that the neutralising levels are low and the serum volume which must be administered is high.
  • This serum antivenom usually of horse origin, is sometimes responsible for severe and even lethal anaphy lactic shocks.
  • the invention provides a synthetic peptide having an amino acid sequence homologous or substantially homologous to that of a naturally occurring peptide animal or plant venom or to an active part thereof save that each cystine residue present in the venom or the active part thereof has been replaced in the synthetic peptide by two o.-amino-butyric acid residues, the synthetic peptide being non-toxic but retaining the antigenic properties of the venom.
  • the synthetic peptides obtained can thus be used to raise specific sera in animals without adverse effects, and also to counteract recent envenomation by administration of non-toxic competitive agents.
  • the invention thus opens routes to vaccines against animal or plant venoms, and treatments for those persons already envenomated.
  • the Boc/benzyl strategy was used, including a systematic double coupling scheme with hydroxybenzotriazole active esters (Boc-AA-OBt).
  • Final cleavage from the resin was effected with anhydrous hydrogen fluoride (1 hour at 0°C).
  • the peptides were washed with diethyl ether and solubilised in water.
  • the synthetic anatoxins were characterised by reverse phase analytical high pressure liquid chromatography (C18), the analysis of amino acids being performed after acid hydrolysis (6N hydrochloric acid, 115°C, 24 hours) and circular dichroism.
  • 8(Abu)-AaH I contained 63 amino acid residues, its primary structure being KRDGYIVYPNN(Abu)VYH(Abu)VPP(Abu)DGL(Abu)KKNGGSSGS(Abu)SFLVPSGLA(A bu)W(Abu)KDLPDNVPIKDTSRK(Abu)T (SEQ ID NO. 1).
  • 8(Abu)-AaH II contained 63 amino acid residues, its primary structure being VKDGYIVDDVN(Abu)TYF(Abu)GRNAY(Abu)NEE(Abu)TKLKGESGY(Abu)QWASPYG NA(Abu)Y(Abu)KLPDHVRTKGPGR(Abu)H-NH 2 (SEQ ID NO. 2).
  • the synthetic anatoxins 8(Abu)-AaH I and 8(Abu)-AaH II were injected into mice by the intracerebro ventricular route at doses of 200 ⁇ g. No toxic effects were observed. Repeated subcutaneous injections of 8(Abu)-AaH II did not elicit any sign of toxicity in mice.
  • mice were injected with 8(Abu)-AaH II.
  • the mice were subcutaneously injected with five times the LD 50 of the natural toxin AaH II. No symptoms of toxicity were observed.
  • the mice were again injected subcutaneously with the natural toxin AaH II, this time in the amount of twelve times the LD 50 . Again the treated animals did not present any clinical or biological sign of toxicity.
  • the animals were thus immunised against Androctonus australis Hector (AaH II) natural toxin.
  • the Abu peptides according to the invention retain the antigenic properties of the natural toxins but do not present the neurotoxic properties observed with the natural venom proteins.
  • Lys Arg Asp Gly Tyr lie Val Tyr Pro Asn Asn Xaa Val Tyr His Xaa 1 5 10 15
  • Val Lys Asp Gly Tyr lie Val Asp Asp Val Asn Xaa Thr Tyr Phe Xaa 1 5 10 15

Landscapes

  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Insects & Arthropods (AREA)
  • Organic Chemistry (AREA)
  • Biochemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Zoology (AREA)
  • Toxicology (AREA)
  • Biophysics (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)

Abstract

L'invention concerne des peptides de synthèse présentant des séquences d'acides aminés homologues ou sensiblement homologues à ceux se trouvant naturellement dans les venins de plantes ou d'animaux, à la différence que chaque résidu de cystine présent dans le venin a été remplacé dans le peptide de synthèse par deux résidus d'acide α-amino-butyriques. Les peptides de synthèse sont non toxiques mais conservent les propriétés antigéniques du venin. Ils peuvent, par conséquent, être utilisés pour préparer des vaccins contre le venin, et également traiter des personnes déjà envenimées.
PCT/EP1997/007333 1996-12-31 1997-12-30 DERIVES α-AMINO-BUTYRATE DES VENINS WO1998029445A1 (fr)

Priority Applications (2)

Application Number Priority Date Filing Date Title
GB9915067A GB2335923B (en) 1996-12-31 1997-12-30 Amino-butyrate derivatives of venoms
AU58611/98A AU5861198A (en) 1996-12-31 1997-12-30 Alpha-amino-butyrate derivatives of venoms

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GBGB9627115.0A GB9627115D0 (en) 1996-12-31 1996-12-31 Alpha-amino-butyrate derivatives of venoms
GB9627115.0 1996-12-31

Publications (1)

Publication Number Publication Date
WO1998029445A1 true WO1998029445A1 (fr) 1998-07-09

Family

ID=10805140

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/EP1997/007333 WO1998029445A1 (fr) 1996-12-31 1997-12-30 DERIVES α-AMINO-BUTYRATE DES VENINS

Country Status (3)

Country Link
AU (1) AU5861198A (fr)
GB (2) GB9627115D0 (fr)
WO (1) WO1998029445A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020596A2 (fr) * 2000-09-04 2002-03-14 Cellpep S.A. Maurotoxine, derives pi1 et hstx1

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
CHAVEZ-OLORTEGUI E.A.: "In vivo protection against scorpion toxins by liposomal immunization", VACCINE., vol. 9, no. 12, December 1991 (1991-12-01), GUILDFORD GB, pages 907 - 910, XP002064838 *
SABATIER E.A.: "Synthesis and characterization of leiurotoxin I lacking one disulfide bridge", BIOCHEMISTRY, vol. 35, no. 33, 20 August 1996 (1996-08-20), EASTON, PA US, pages 10641 - 10647, XP002064839 *
XU E.A.: "One-disulfide intermediates of apamin exhibit native-like structure", BIOCHEMISTRY, vol. 33, no. 17, 1994, EASTON, PA US, pages 5253 - 5261, XP002064840 *
ZENOUAKI E.A.: "In vivo protection against Androctonus australis hector scorpion toxin and venom by immunization with a synthetic analog of toxin II", VACCINE., vol. 15, no. 2, February 1997 (1997-02-01), GUILDFORD GB, pages 187 - 194, XP004054370 *

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002020596A2 (fr) * 2000-09-04 2002-03-14 Cellpep S.A. Maurotoxine, derives pi1 et hstx1
WO2002020596A3 (fr) * 2000-09-04 2002-08-01 Cellpep Sa Maurotoxine, derives pi1 et hstx1
US7829666B2 (en) 2000-09-04 2010-11-09 Cellpep Pharma Inc. Maurotoxin, PI1 and HSTX1 derivatives

Also Published As

Publication number Publication date
GB2335923B (en) 2001-03-14
GB2335923A (en) 1999-10-06
AU5861198A (en) 1998-07-31
GB9915067D0 (en) 1999-08-25
GB9627115D0 (en) 1997-02-19

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