WO2011138489A1 - Utilisation d'hydrolysats de caséines en tant qu'antiviraux - Google Patents

Utilisation d'hydrolysats de caséines en tant qu'antiviraux Download PDF

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Publication number
WO2011138489A1
WO2011138489A1 PCT/ES2011/070318 ES2011070318W WO2011138489A1 WO 2011138489 A1 WO2011138489 A1 WO 2011138489A1 ES 2011070318 W ES2011070318 W ES 2011070318W WO 2011138489 A1 WO2011138489 A1 WO 2011138489A1
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Prior art keywords
virus
seq
genus
casein hydrolyzate
preferred
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PCT/ES2011/070318
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English (en)
Spanish (es)
Inventor
Isidra RECIO SÁNCHEZ
Sylvia RODRÍGUEZ SAINT-JEAN
Sara Isabel PÉREZ PRIETO
Iván LÓPEZ EXPÓSITO
Ana Isabel DE LAS HERAS SÁNCHEZ
José Angel GÓMEZ RUIZ
Mercedes Ramos González
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Consejo Superior De Investigaciones Científicas (Csic)
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Publication of WO2011138489A1 publication Critical patent/WO2011138489A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/01—Hydrolysed proteins; Derivatives thereof
    • A61K38/012—Hydrolysed proteins; Derivatives thereof from animals
    • A61K38/018—Hydrolysed proteins; Derivatives thereof from animals from milk
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses

Definitions

  • the present invention is within biology and medicine, and specifically refers to the use of enzymatic hydrolysates of milk caseins as antivirals, and in particular against salmonid viruses, to the compositions containing said hydrolysates, and to their process of obtaining.
  • lactoferrin milk protein and chemical modifications thereof aimed at modifying the surface charge of the protein have demonstrated remarkable activity against human immunodeficiency virus type 1 (HIV), or human cytomegalovirus (HCMV) (Flor ⁇ s et al., Curr. Pharm. Design é, 2003, 1257-1275; Pan et al., 2006. Int. Dairy J. 16, 1252-1261).
  • HMV human immunodeficiency virus
  • HCMV human cytomegalovirus
  • Other milk proteins have demonstrated antiviral activity only after their chemical modification to give them a markedly negative or positive charge.
  • Lactoferrin has antiviral activity against Herpes simplex type 1 and 2 (Hasegawa et al., 1994. Jpn. J. Med. Sci. Biol. 47, 73-85), adenovirus (Arnold et al., 2002. Antiviral Res 53 , 153-158) HIV virus (Harmesen et al. J. Infect.Dis 172, 1995, 380-388; Puddu et al., 1998. Int. J. Biochem. Cell B. 30, 1055-1063; Van der Strate et al., 2000. Viral Inmunol 12, 197-203) hepatitis C virus (Tanaka et al., 1999.
  • Glycomacropeptide f (106-169) inhibits hemagglutination of influenza virus (Kawasaki et al., 1993. Bios Biotech & Biochem, 57, 1214-1215). So far, most studies with proteins and food peptides have been done with human viruses, so there is no data on the activity of these proteins or their chemical modifications against viruses involved in fish diseases. Viruses affecting teleost fish offer great interest as aquaculture has intensified and diversified throughout the world, and movements of live animals or their products have accelerated the accidental spread of diseases, which cause serious economic losses in this sector. .
  • viruses constitute an innovative model for the determination of the biological activity of peptides and food proteins, which may have antiviral or immunostimulatory characteristics and that could constitute a resource as a drug or as an adjuvant for DNA vaccines.
  • the approach of the use of possible antivirals in fish of consumption has not been developed because they are toxic molecules, or little active or too expensive.
  • Viruses that affect teleost fish such as Aquabirnavirus, infectious pancreatic necrosis virus (IPNV) and Novirhabbdovirus, infectious hematopoietic necrosis virus (IHNV) cause systemic infections and cause high mortality in trout and other salmonids being responsible for serious losses economic in the aquaculture sector worldwide. IHNV can cause losses greater than 90% in affected farms and is endemic in the North-East Pacific of North America extending to other areas and countries (La Patra et al., 1996. Ann. Rev. Fish Dis. 6, 15- 28 .; Enzmann et al., 1992. Bull. Eur. Ass. Fish. Pathol. 12, 185 .; Bootland and Leong, Fish Diseases and Disorders. Vol.
  • IPNV IP-like virus
  • the IPNV was isolated for the first time in North America in 1960 and has spread to Europe and Japan. This virus has been isolated from other species of non-salmonid fish as well as crustaceans and mollusks and is the most prevalent in Spanish facilities (Wolf, Fish Viruses and Fish Diseases., 1988, 1 15-157, Rodr ⁇ guez et al., 1997, J Aquatic Animal Health 9: 295-300. Rodr ⁇ guez ef al., 2003. Adv Virus Res 62, 1 13- 165.
  • hydrolysates of caseins and peptides derived from the alpha s 2 -casein could serve, in addition to being part of food products or pharmaceuticals, for the treatment and prevention of some diseases; particularly they could act as fish antivirals and be used in aquaculture.
  • the invention extends the applications of milk proteins contributing to their use and revaluation.
  • the present invention provides a series of casein hydrolysates, which contain a series of peptides with antiviral activity, and in particular, with activity against infectious hematopoietic necrosis virus, IHNV and against infectious pancreatic necrosis virus, IPNV
  • a first aspect of the invention relates to the use of a casein hydrolyzate in the preparation of a medicament for the treatment of a viral disease, or alternatively, a casein hydrolyzate for use in the treatment of a viral disease. .
  • the casein hydrolyzate comprises at least one of the peptides that are selected from the list comprising: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEO ID NO: 4, SEO ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, or any of its combinations
  • the casein hydrolyzate comprises at least one of the peptides that are selected from the list comprising: SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 SEQ ID NO: 10, SEQ ID NO: 1 1, or any combination thereof.
  • the casein hydrolyzate comprises at least the sequence peptide SEQ ID NO: 6
  • the viral disease is suffered by a fish, more preferably belonging to the order Salmoniformes, and even more preferably to the genus Salmo or the genus Oncorhynchus.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is infectious pancreatic necrosis virus (infectious pancreatic necrosis virus or IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is the infectious hematopoietic necrosis virus ⁇ infectious hematopoietic necrosis virus or IHNV).
  • viral disease means a disease that is characterized by the clinical manifestation resulting from an infection caused by a virus, and whose invasive and, if appropriate, harmful action has disrupted the biology of the affected host.
  • Methods for the detection of the type of virus that acts as a pathogen are known in the state of the art, such as, but not limited to, through all molecular identification techniques (genetic probes, in situ hybridization, on colonies (colony blotting ) and on membranes (Southern blotting), DNA microarrays and microchips, techniques based on PCR (polymerase chain reaction) such as random PCR, nested PCR and RT-PCR, ligase chain reaction (CSF) ), Q-replicase reaction, cyclic probe technique (CPT), transcription-based amplification: TAS and self-sustained sequence replication (3SR), study of nucleic acid polymorphism, using, for example, restriction analysis ( RFLP and AFLP)., Mitochondrial DNA analysis
  • Birnaviridae is a family of viruses that affects animals. It includes the following genres:
  • Genus Entomobirnavirus type species: Drosophila virus X.
  • Rhabdoviridae is a family of infectious viruses for animals and plants. Among infected animals are insects, fish and mammals, including humans.
  • Rhabdoviridae is a family of infectious viruses for animals and plants. Among infected animals are insects, fish and mammals, including humans. The family includes the following genera:
  • Genus Cytorhabdovirus type species: Lettuce yellow necrosis virus.
  • Genus Ephemerovirus type species: Bovine ephemeral fever virus.
  • Genus Lyssavirus type species: Rabies virus.
  • Genus Novirhabdovirus type species: Infectious hematopoietic necrosis virus.
  • Genus Nucleorhabdovirus type species: Potato yellow dwarf virus.
  • Genus Vesiculovirus type species: Vesicular stomatitis virus.
  • compositions hereinafter composition of the invention, comprising an enzymatic casein hydrolyzate, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to a composition which comprises comprising an enzymatic casein hydrolyzate for use in the treatment of a viral disease.
  • the composition is a pharmaceutical composition.
  • the casein enzyme hydrolyzate of the composition comprises at least one of the peptides that are selected from the list comprising: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO : 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10, SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17, SEQ ID NO: 18, SEQ ID NO: 19, SEQ ID NO: 20, or any combination thereof.
  • casein hydrolyzate comprises at least one of the peptides that are selected from the list comprising: SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9 SEQ ID NO: 10, SEQ ID NO 1 1, or any combination thereof.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • composition of the invention further comprises another active ingredient.
  • composition of the invention further comprises a pharmaceutically acceptable carrier.
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 1, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 1 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 2, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 2 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is the infectious hematopoietic necrosis virus ⁇ infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 3, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 3 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the virus of the Birnaviridae family belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 4, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 4 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (infectious pancreatic necrosis virus or IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 5, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 5 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 6, in the preparation of a medicament for the treatment of a viral disease, or alternatively, the peptide of amino acid sequence SEQ ID NO: 6 for use in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 7, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 7 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdovir ⁇ dae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 8, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 8 for use in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdovir ⁇ dae.
  • the virus of the family Rhabdovir ⁇ dae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 9, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 9 for use in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 10, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 10 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 1 1, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 1 for its Use in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 12, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 12 for use in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • IPNV pancreatic necrosis virus
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 13, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 13 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 14, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 14 for use in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 15, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 15 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is the infectious hematopoietic necrosis virus ⁇ infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 16, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 16 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 17, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 17 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (infectious pancreatic necrosis virus or IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 18, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 18 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 19, in the preparation of a medicament for the treatment of a viral disease, or alternatively, the peptide of AMQ sequence SEQ ID NO: 19 for use in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • Another aspect of the invention relates to the use of the amino acid sequence peptide SEQ ID NO: 20, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to the amino acid sequence peptide SEQ ID NO: 20 for use. in the treatment of a viral disease.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • the peptides of the enzymatic casein hydrolyzate of the invention are peptides, and can act as active ingredients in compositions, preferably in pharmaceutical compositions.
  • active ingredient means any component that potentially provides a pharmacological activity or other different effect (metabolic activity, immunological, 3) in the diagnosis, cure, mitigation, treatment, or prevention of a disease or medical condition, or that affects the structure or function of the body of man or other animals.
  • compositions comprising a peptide that is selected from the list comprising: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO:
  • SEQ ID NO: 10 SEQ ID NO: 1 1, SEQ ID NO: 12, SEQ ID NO: 13, SEQ ID NO: 14, SEQ ID NO: 15, SEQ ID NO: 16, SEQ ID NO: 17 , SEQ ID NO: 18, SEQ ID NO: 19, and SEQ ID NO: 20, or any combination thereof, in the preparation of a medicament for the treatment of a viral disease, or alternatively, to a composition comprising a peptide which is selected from the list comprising: SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7 , SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO:
  • the peptide is selected from the list comprising: SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6, SEQ ID NO: 7, SEQ ID NO: 8, SEQ ID NO: 9, SEQ ID NO: 10. and SEQ ID NO: 1 1, or any combination thereof.
  • the peptide of the invention can be formulated in a composition, useful for the treatment of a viral disease.
  • the use of peptides as potential therapeutic agents has the advantage of their high specificity and high activity, generally presenting low toxicity and few side effects. In addition, they do not accumulate in the body, since they have a relatively short half-life (Adresi and Soto, 2002. Current Medicinal Chemistry 9: 963-978; L ⁇ en & Lowman 2003. TRENDS in Biotechnoiogy 21: 556-562).
  • the composition is a pharmaceutical composition.
  • the viral disease is caused by a virus of the Birnaviridae family.
  • the Birnaviridae family virus belongs to the genus Aquabirnavirus.
  • the virus of the genus Aquabirnavirus is the infectious pancreatic necrosis virus (IPNV).
  • the viral disease is caused by a virus of the family Rhabdoviridae.
  • the virus of the family Rhabdoviridae belongs to the genus Novirhabdovirus.
  • the virus of the genus Novirhabdovirus is infectious hematopoietic necrosis virus (infectious hematopoietic necrosis virus or IHNV).
  • composition of the present invention can therefore be formulated for administration to an animal, and more preferably to a mammal, including man, in a variety of ways known in the state of the art.
  • it can be formulated for administration to a fish, more preferably belonging to the order Salmoniformes, and even more preferably to the genus Salmo or the genus Oncorhynchus.
  • they may be, without limitation, in sterile aqueous solution or in biological fluids, such as serum.
  • Aqueous solutions may be buffered or unbuffered and have additional active or inactive components.
  • compositions can be prepared for administration in solid form.
  • compositions may be combined with various inert vehicles or excipients, including but not limited to; binders such as microcrystalline cellulose, gum tragacanth, or gelatin; excipients such as starch or lactose; dispersing agents such as alginic acid or corn starch; lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide; sweetening agents such as sucrose or saccharin; or flavoring agents such as peppermint or methyl salicylate.
  • binders such as microcrystalline cellulose, gum tragacanth, or gelatin
  • excipients such as starch or lactose
  • dispersing agents such as alginic acid or corn starch
  • lubricants such as magnesium stearate, glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin
  • flavoring agents such as peppermint or methyl salicylate.
  • compositions and / or their formulations may be administered to an animal, including a mammal and, therefore, to man, in a variety of ways, including, but not limited to, intraperitoneal, intravenous, intramuscular, subcutaneous, intracecal, intraventricular, oral. , enteral, parenteral, intranasal or dermal.
  • the administration is oral.
  • the dosage to obtain a therapeutically effective amount depends on a variety of factors, such as age, weight, sex, tolerance, ... of the animal, including man.
  • the term “therapeutically effective amount” refers to the amount of peptides, or prodrugs, derivatives or analogs of said peptide that produce the desired effect and, in general, will be determined, among other causes, by the characteristics of said prodrugs, derivatives or analogs and the therapeutic effect to be achieved.
  • the "adjuvants” and “pharmaceutically acceptable carriers” that can be used in said compositions are the vehicles known to those skilled in the art.
  • the term "medicine” refers to any substance used for prevention, diagnosis, relief, treatment or cure of diseases in man and animals, and even more preferably in fish, and even more preferably in organisms of the order Salmoniformes. In the context of the present invention, therefore, the pharmaceutical composition of the invention would also be a medicament.
  • fish is understood as aquatic vertebrate animals, generally ectothermal, mostly covered with scales and equipped with fins, which allow their movement in the aquatic environment. Taxonomically they belong to three groups: agnatos or fish without jaws, chondrites or cartilaginous and osteictiose fish or bony fish.
  • Salmoniformes are cellular organisms, of the Eukaryota Superein, Metazoa kingdom, Phylum Chordata, Gnathostomata superclass, Actinopterygii class.
  • the Salmoniformes order includes the Galaxiidae, Retropinnidae, Osmeridae, and Salmonidae families. Within the Salmonidae family are the genera Coregonus, Prosopium, Stenodus, Brachymystax, Hucho, Oncorhynchus, Parahucho, Salmo, Salvelinus, Salvethymus and Thymallus.
  • Fig. 1 Reduction of the infective titer against the IHNV virus with protein hydrolysates obtained after different times of hydrolysis using doses of 100 ⁇ g / ml of each hydrolyzate.
  • A Casein hydrolyzate
  • B ⁇ -casein hydrolyzate
  • C Ace 2 -casein hydrolyzate
  • D As-casein hydrolyzate.
  • Fig. 2 Viral performance over time after infecting with IHNV the cells in the presence and absence of the total casein and S 2-casein hydrolysates at a dose of 100 ⁇ .
  • Fig. 3 Percentage of cells infected with IHNV through the detection of antiviral antigens at 48 hours post-infection by flow cytometry, in the control of non-infected cells (A), in control of infected cells (B) and in the Infected cells treated with the hydrolysates of total casein and S 2-casein.
  • Fig. 4 Infectious titer against IHNV incorporating the hydrolysates to the test 30 minutes before infection, at the same time as the infection, or 60 minutes after infection.
  • Fig. 5 FPLC analysis of a s2 -CN hydrolyzate
  • Fig. 6 Percentage of inhibition of the IHNV virus and reduction of the infective titer using different concentrations of the C, D and E fractions obtained by cation exchange (according to nomenclature used in Table 2). (A)% IHNV virus inhibition. (B) IHNV virus infectious titer reduction.
  • Fig. 7 Percentage of inhibition and reduction of the infective titer against the IHNV virus with different concentrations of the peptide at s2 -casein f (183-207), chemically synthesized, and the peptide hydrolyzate of a s2 -casein from which said peptide comes.
  • the isoelectric casein was prepared by precipitation at pH 4.6 of whole milk by adding 2 M HCI to pH, 4.6 followed by centrifugation at 4500 g for 15 min.
  • the casein precipitate was washed three times with acidified water and subsequently lyophilized.
  • the fractions of oc s -casein, ⁇ -casein and -casein came from different commercial houses
  • the o3 ⁇ 42-CN was prepared following the method of Vreeman and Van Riel, 1990 (Neth Milk Dairy Journal 44,43-48) with some modifications.
  • a solution in milli-Q ® water (Millipore, Billerica, USA) was prepared from the lyophilisate casein at a concentration of 8% (w / v). With the help of NaOH, the pH was increased to 7, DTT ⁇ 1.2%, w / w) was added and stirred at 5 S C to achieve complete casein dissolution.
  • Phases A and B consisted of 10 mM NH 4 HC0 3 (adjusted to pH 7.0 with HCOOH) and 1.5 M NH 3 , respectively. Samples were prepared in phase A at a concentration of 5 img / mL, injecting a volume of 5 mL using a 50 mL Superloop TM (Pharmacia). A flow of 5 mL / min was used.
  • the different fractions collected from the FPLC were analyzed by RP-HPLC-MS / MS.
  • a Ski-LC equipment (Bruker Daltonik GMBH, Bremen, Germany) was used.
  • the HPLC equipment (series 1 100) consisted of a quaternary pump, an automatic injector, an eluent degassing system and a variable wavelength ultraviolet detector (Agilent Technologies, Waldbronn, Germany) coupled in line to a spectrometer Esquire 3000 ion trap masses (Bruker Daltonik).
  • the column was a Hi-Pore C18 column (250 x 4.6 mm di, 5 ⁇ particle size) (Bio-Rad Laboratories, Richmond, CA, USA).
  • Solvent A was a mixture of water and trifluoroacetic acid (1000: 0.37) and solvent B a mixture of acetonitrile and trifluoroacetic acid (1000: 0.27).
  • 50 ⁇ of prepared sample was injected at a concentration of 4.5 mg / ml.
  • a flow of 0.8 ml / min was used, with a linear gradient from 0% to 50% of solvent B in 60 minutes
  • the eluent was monitored at 214 nm and the sample flow to the mass spectrometer nebulizer was 275 ⁇ / min.
  • ESI ionization used N 2 as a fogging agent (8 L / min), fogging pressure of 60 psi, drying temperature of 350 Q C and a capillary voltage of 4 KV.
  • the mass spectra were acquired in the range of 100-2500 m / z and a fragmentation ramp between 0.3 and 2 V was used.
  • Esquire ControlTM 5.0 program was used and to identify the sequence of the different peptides were used Data AnalysisTM 3.0, Sequence EditorTM 2.1 and BiotoolsTM 2.1 software all from Bruker Daltonik (Bruker DaltoniK, Germany).
  • the BF-2 cell line was chosen because of its susceptibility to various viruses. Rodr ⁇ guez Saint-Jean & Pérez Prieto, 2006 [Veterinary Immunology and Immunopathology 110: 1-10). This cell line comes from sunfish fry, Lepomis macrochirus and was purchased from the American Type Culture Collection (ATCC CRL 1681). The cells were grown in Leiboviz growth medium (L15, Gibco, Invitrogen, Barcelona) at 25 Q C, supplemented with 100 units / mL of penicillin, 100 ⁇ g / mL of streptomycin, 2 mM of L-glutamine and 10% serum fetal bovine (FBS, Gibco). For the maintenance of the cell monolayer, the same medium was used but decreasing the percentage of fetal serum to 2%.
  • Leiboviz growth medium L15, Gibco, Invitrogen, Barcelona
  • FBS serum fetal bovine
  • the cells 24 hours after planting and with a subconfluent monolayer, were infected with 1000 TCID 50 / ml virus and incubated at 15 or 20 e C (depending on the virus) until the cytopathic effects (CPE) produced by the virus affected the entire cell monolayer. At that time the supernatants were collected, centrifuged at low speed (900 g) for 5 minutes to remove the cell debris and aliquots of the virus suspension were distributed in eppendorff tubes that were stored at -80 S C until use. The infective title of the pass Virus was determined by calculating the 50% infective dose (TCID 50 / mL) detailed below.
  • the viruses used come from the ATCC and were the infectious pancreatic necrosis virus (IPNV, ATCC VR1318) and the infectious hematopoietic necrosis virus (IHNV, ATCC VR714).
  • IPNV infectious pancreatic necrosis virus
  • IHNV infectious hematopoietic necrosis virus
  • the amount of virus used in the infection should be sufficient so that at 3 days post-infection (IPNV) and 7 days (IHNV) total lysis is observed in the cells not treated with compound (virus control).
  • the plates were incubated at 15 Q C for 3-7 days and after removal of the medium, the monolayers were stained with a crystal violet solution 1% (w / v) in 20% ethanol for 10 min After washing and drying in air the absorbance was measured in a microplate reader (Bio-Rad ®) at 590 nm. The results are presented as percentages of c surviving cells, where 100% represents the absorbance of the control cells.
  • the cytotoxic concentration of the compound that causes 50% inhibition of cell growth is called CT 50.
  • the antiviral activity is determined by the ability of the compounds to inhibit the cytopathic effects (lysis) of the virus and protect the cell monolayer and is calculated by the percentage of viable cells after infection.
  • BF-2 cells approximately 10 5 ml "1 ) cultured in 48-well plates were infected with 1000 TCID 50 / ml virus and different concentrations of the hydrolyzate or its fractions or peptides diluted in maintenance medium. The cultures were incubated at the optimum temperatures for each virus 20 ° C for IPNV and 15 ° C for IHNV.
  • CPE cytopathic effects
  • BF-2 cells approximately 10 5 mL "1
  • TCID 50 / ml virus in the presence of different concentrations of the compounds, diluted in maintenance medium.
  • controls cells were maintained untreated but infected (control virus) and untreated and uninfected cells (control cells) The cultures were incubated at the optimum temperatures for each virus.
  • the monolayers were stained and the infective titer was calculated.
  • the infective titer is calculated by diluting the end point, which is the highest (decimal) dilution in which the virus infects 50% of the inoculated wells.
  • the titer is expressed as the reciprocal of this dilution, in infectious units (TCID 50 ) ⁇ Tissue culture infective dose 50%) per ml_.
  • Example 1 Antiviral activity against salmonid viruses (IPNV and IHNV) of total casein hydrolysates and hydrolysates of different casein fractions.
  • Table 1 presents the results obtained on the evaluation of the antiviral activity against salmonid viruses (IPNV and IHNV) of total casein hydrolysates and hydrolysates of different casein fractions with hydrolysis times between 0.5 to 24 hours. These results show that hydrolysis with pepsin of the casein fraction generates peptides with activity against the IHNV virus. The highest therapeutic index with a value of 30 was reached in the total casein hydrolyzate obtained after 3 hours of hydrolysis, followed by the total casein hydrolyzate with a shorter hydrolysis time (therapeutic index of 6) (products 1 to 5 , from Table 1).
  • CT 5 () is the dose or concentration of the compound that has 50% toxicity in cell cultures.
  • MIC 50 is the concentration of the compound that inhibits 50% the cytopathic effects of the virus
  • Fig. 1 shows the reduction of the infectious titer of the IHNV virus determined with a dose of 100 g / m ⁇ of the hydrolysates. The best results were obtained with the total casein hydrolysates and with the hydrolysates obtained from the fraction of a S 2-casein. A reduction of 1.5-2.5 log of the infective titer is observed for casein hydrolysates obtained during the first three hours of hydrolysis. For hydrolysates obtained from oc S 2-casein activity was observed up to 7 hours of hydrolysis, the most active hydrolyzate being obtained after 3 hours (2.5 log).
  • Figure 3 shows the percentage of infected cells in the control of infected cells, in the control of non-infected cells and in infected cells treated with hydrolysates. At 48 hours, the percentage of infected cells in the samples treated with o ⁇ -casein hydrolyzate was similar to that found in uninfected cells.
  • hydrolysates were active in the early stages of the virus cycle or during viral replication, they were performed addition time trials, in which the hydrolyzate was incorporated into the test 30 minutes before infection, at the same time as the infection, or 60 minutes after infection. It was observed that the greatest reduction in the infectious titer against IHNV was obtained when the hydrolisate was incorporated at the same time that the infection occurs and that, therefore, the hydrolyzed ones must act during the adsorption of the viruses to the cells ( Figure 4).
  • Example 2 Antiviral activity against IHNV salmonid virus of different fractions of the cc S 2-casein hydrolyzate.
  • the majority peptide in this fraction is fragment 183-207 of the oc s2 -casein, a peptide with a marked cationic character and that had been previously described for its antibacterial activity against Gram-positive and Gram-negative bacteria (Recio and Visser, Biochim Biophys Acta 1428, 1999, 314-326; WO 00/15655).
  • the antiviral activity of this fragment had not been described.
  • the activity of other fragments cannot be ruled out since fraction D also exhibits remarkable antiviral activity and does not contain this fragment.
  • the activity of the peptide against the IHNV virus was evaluated both by determining the percentage of inhibition and reducing the infective titer. These activity values for the pure peptide obtained by chemical synthesis are shown in the graphs of Figure 7, in Comparison with the activity values obtained for the hydrolyzate of a S 2-casein from which the peptide is derived. It is observed that peptide 183-207 is active against the IHNV virus and the determination of the infective titer can be concluded that it is one of the peptides responsible for the hydrolyzate activity although the additive or synergistic activity of other peptides present cannot be ruled out. in the hydrolyzate

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Abstract

L'invention concerne l'utilisation d'hydrolysats enzymatiques de caséines lactées, et de compositions qui contiennent lesdits hydrolysats, en tant qu'antiviraux. Lesdits hydrolysats et lesdites compositions sont particulièrement utiles contre les virus affectant les salmonidés, et en particulier contre le virus de la nécrose pancréatique infectieuse (VNPI) et le virus de la nécrose hématopoïétique infectieuse (VNHI).
PCT/ES2011/070318 2010-05-06 2011-05-04 Utilisation d'hydrolysats de caséines en tant qu'antiviraux WO2011138489A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2444299A1 (es) * 2012-08-23 2014-02-24 Nutrición Técnica Deportiva, S.L. Uso de un hidrolizado de caseina como agente antiherpético
ES2544153A1 (es) * 2014-02-24 2015-08-27 Ntd Labs, S.L. Uso de un hidrolizado de caseína como agente antiviral

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032727A1 (fr) * 1994-05-26 1995-12-07 Abbott Laboratories Inhibition de l'infection de cellules de mammiferes par le virus respiratoire syncytial
US20040167073A1 (en) * 2000-03-01 2004-08-26 Chay 13 Medical Research Group N.V. Casein derived peptides and uses thereof
WO2006118459A1 (fr) * 2005-04-29 2006-11-09 Campina Nederland Holding B.V. Peptides antiviraux

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1995032727A1 (fr) * 1994-05-26 1995-12-07 Abbott Laboratories Inhibition de l'infection de cellules de mammiferes par le virus respiratoire syncytial
US20040167073A1 (en) * 2000-03-01 2004-08-26 Chay 13 Medical Research Group N.V. Casein derived peptides and uses thereof
WO2006118459A1 (fr) * 2005-04-29 2006-11-09 Campina Nederland Holding B.V. Peptides antiviraux

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
RECIO, I. ET AL.: "Identification of two distinct antibacterial domains within the sequence of bovine as2-casein.", BIOCHIMICA ET BIOPHYSICA ACTA, vol. 1428, no. 2-3, August 1999 (1999-08-01), pages 314 - 326, XP004276453, DOI: doi:10.1016/S0304-4165(99)00079-3 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES2444299A1 (es) * 2012-08-23 2014-02-24 Nutrición Técnica Deportiva, S.L. Uso de un hidrolizado de caseina como agente antiherpético
ES2544153A1 (es) * 2014-02-24 2015-08-27 Ntd Labs, S.L. Uso de un hidrolizado de caseína como agente antiviral
WO2015125067A1 (fr) * 2014-02-24 2015-08-27 Ntd Labs, S. L. Utilisation d'un hydrolysat de caséine en tant qu'agent antiviral
US10772927B2 (en) 2014-02-24 2020-09-15 Ntd Labs, S.L. Use of a casein hydrolysate as an antiviral agent

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